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Oral Vancomycin Monotherapy Versus Combination Therapy in Solid Organ Transplant Recipients With Uncomplicated Clostridium difficile Infection: A Retrospective Cohort Study
Oral Vancomycin Monotherapy Versus Combination Therapy in Solid Organ Transplant Recipients With Uncomplicated Clostridium difficile Infection: A Retrospective Cohort Study G.B. Korayema,b,*, K. Eljaalyb,c, K.R. Matthiasb,d, and T.T. Zangenehd,e a Department of Pharmaceutical Practices, Princes Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia; bDepartment of Pharmacy Practice and Science, University of Arizona, Tucson, Arizona; cDepartment of Clinical Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia; dBanner - University Medical Center Tucson, Tucson, Arizona; and the eDivision of Infectious Diseases, Department of Medicine, University of Arizona, Tucson, Arizona
ABSTRACT Introduction. Solid organ transplant (SOT) recipients are at high risk of Clostridium difficile infection (CDI) and CDI recurrence due to their suppressed immune systems and antibiotic exposure. A combination of metronidazole and oral vancomycin is often prescribed for SOT recipients with uncomplicated CDI despite any clinical practice guidelines supporting the need for combination therapy. This study aims to compare the CDI recurrence rates of metronidazole/vancomycin combination therapy to oral vancomycin monotherapy in SOT recipients after a first episode of uncomplicated CDI. Methods. A single-center retrospective cohort study evaluated SOT recipients diagnosed with uncomplicated CDI who were treated with vancomycin monotherapy or vancomycin/ metronidazole combination therapy. The primary endpoint was CDI recurrence defined as a second CDI episode within 8 weeks of completing index CDI therapy. The secondary endpoints were time between the end of CDI therapy and recurrence, length of total hospitalization after the index CDI, and length of hospitalization after index CDI diagnosis. Results. Fifteen patients (25%) of 61 subjects experienced CDI recurrence. There was no statistically significant difference in CDI recurrence rate between the vancomycin monotherapy group and combination therapy group (23% versus 27%, respectively; P ¼ .715). The median total length of hospitalization between the vancomycin monotherapy and combination therapy groups was statistically significant (9 versus 14 days, respectively; P ¼ .047). Discussion. There was no difference found in recurrence rate between oral vancomycin monotherapy versus combination therapy. The study result weakens the practice of prescribing combination therapy for uncomplicated CDI in SOT recipients.
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LOSTRIDIUM difficile infection (CDI) is a common cause of hospital-acquired infection and is associated with increasing morbidity and mortality [1e3]. Even though most patients with CDI will respond to therapy with either metronidazole, vancomycin (oral), or fidaxomicin, the number of patients with CDI recurrence has dramatically increased over the years [4]. Recurrent CDI can be caused by either relapse due to the original infecting strain or reinfection with a new strain [5]. Solid organ transplant (SOT) recipients are at high risk for CDI recurrence due to suppressed immune systems, prolonged hospitalizations, broad-spectrum ª 2017 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, 50, 137e141 (2018)
antimicrobial use, leukopenia, post-transplantation hypogammaglobulinemia, polyclonal antibodies induction therapy, and high-dose corticosteroid use [6e8]. The reported rate of CDI recurrence in patients after SOT ranges from 8.5% to 40%, which is higher than the reported rate of 10 to 20% in the general population [8e11].
*Address correspondence to Ghazwa B. Korayem, PharmD, University of Arizona, 1295 N. Martin, PO Box 210202, Tucson, Arizona. E-mail: [email protected] 0041-1345/17 https://doi.org/10.1016/j.transproceed.2017.11.016
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Although metronidazole is the first-line agent for treatment of mild-to-moderate CDI [12], metronidazole monotherapy is often not prescribed by clinicians due to their consideration of the interaction between tacrolimus and metronidazole in patients with SOT. Instead, the combination of metronidazole and oral vancomycin is often prescribed for SOT patients and other perceived fragile or immunocompromised patients with uncomplicated CDI, despite any clinical practice guidelines supporting combination therapy in this population [12e14]. Whereas this combination therapy is currently recommended only for complicated, severe CDI with ileus, this tendency is likely due to clinicians’ hesitation to follow guidelines that do not specifically address how to treat SOT recipients [12,13]. Because SOT is a common exclusion criterion in studies comparing CDI treatment regimens, there are limited published data regarding treatment of CDI in this population. Recurrence rate is one of the major outcomes that should be assessed when evaluating antibiotics used for CDI therapy. Therefore, this study aims to compare the CDI recurrence rates of metronidazole/vancomycin combination therapy to oral vancomycin monotherapy in SOT recipients after the first episode of uncomplicated CDI. PATIENTS AND METHODS Study Design and Patient Population In this retrospective cohort study, institutional review board approval was obtained. CDI recurrence rates were evaluated in SOT recipients who received oral vancomycin monotherapy or a combination of vancomycin/metronidazole for an initial CDI episode. The attending physician determined CDI treatment and duration while the patient was admitted to a tertiary care, academic medical center between November 1, 2013, and October 30, 2016. Patients were followed for 8 weeks after completion of CDI therapy to assess CDI recurrence. Exclusion criteria included <18 years of age, if another CDI occurred within 8 weeks before study period, hematopoietic stem cell transplantation or use of fecal microbiota transplantation, metronidazole monotherapy, and use of fidaxomicin or rifaximin during initial CDI therapy. Patients who met the Society for Healthcare Epidemiology of America’s (SHEA) and Infectious Diseases Society of America (IDSA) criteria for severe and complicated CDI [12], experienced treatment cross-over, or died within the follow-up period (8 weeks) were also excluded.
Endpoints and Definitions The primary endpoint of CDI recurrence was defined as experiencing a second CDI episode within 8 weeks of completing index CDI therapy [13]. A CDI episode was defined as having both 3 loose stools per day and microbiological evidence of the Clostridium difficile toxin isolate by enzyme-linked immunosorbent assay or polymerase chain reaction testing. The secondary endpoints were time between the end of CDI therapy and recurrence, length of total hospitalization after the index CDI, and length of hospitalization after index CDI diagnosis. CDI disease severity definitions and therapy recommendations were based on SHEA and IDSA guidelines [12]. Mild-moderate CDI was defined as having a white blood cell (WBC) count of <15,000 cells/mL and serum creatinine level (SCr) of <1.5 times premorbid levels. Severe CDI was defined by either having a WBC 15,000
KORAYEM, ELJAALY, MATTHIAS ET AL cells/mL or SCr >1.5 times premorbid levels. Uncomplicated CDI was defined as not meeting IDSA or American College of Gastroenterology (ACG) criteria for complicated CDI, which include hypotension, shock, ileus, megacolon, significant abdominal distention, colonic perforation, colectomy, intensive care unit admission, fever 38.5 C, mental status changes, WBC 35,000 cells/mm3 or <2000 cells/mm3, serum lactate concentrations >2.2 mmol/L, or end organ failure (mechanical ventilation, renal failure). Patients who received oral vancomycin and metronidazole concomitantly at any point during therapy were considered to be part of the combination group, whereas patients who received oral vancomycin alone without switching between agents “crossover” were considered to be part of the monotherapy group.
Data Analysis All patient charts were reviewed using a standard data collection, and data was entered into a standard electronic data collection form using the web-based application REDCap [15] (REDCAP version 8.1.1 Nashville,TN,USA hosted at University of Arizona). Statistical analyses were performed with SPSS software, version 24 (IBM, Armonk, New York, United States). Non-normally distributed continuous data were described using the median (interquartile range [IQR]), and differences between the study groups were compared using a 2-tailed Mann-Whitney U test. Categorical data were described as counts (%), and a Fisher’s exact or c2 test was used for comparison. We adjusted for confounding variables and used a multivariable logistic regression analysis to assess CDI recurrence. If a variable was considered clinically relevant or its P value was <.2, that variable was considered for the regression analysis.
RESULTS
During the initial screening of 94 patients, patients were excluded for the following reasons: complicated CDI (n ¼ 3), recurrent CDI with initial CDI before study period (n ¼ 1), death unrelated to CDI during the follow-up period (n ¼ 2), initial treatment crossover (n ¼ 6), and receiving metronidazole (n ¼ 21). This left a final total of 61 patients, with 35 in the oral vancomycin monotherapy arm and 26 in the combination vancomycin/metronidazole therapy arm. The demographic and baseline characteristics of these patients are described in Table 1. There were no statistically significant differences between the two study groups, except patients in the vancomycin monotherapy arm were more likely to have underwent lung transplantation or received proton-pump inhibitors after CDI therapy and less likely to have received third/fourth generation cephalosporins during the 8-week follow-up period. The median age of patients was 60 years and the proportion of patients 64 years of age was approximately 30%. The most common type of organ transplantation was kidney, which was found in half of the patients. The ratio of having mild-moderate CDI to severe CDI was 3:2. The NAP1/B1/027 strain of Clostridium difficile was found in 13% of patients. The median CDI antibiotic therapy duration was 16 days. The study outcomes are presented in Table 2. Fifteen patients (25%) experienced CDI recurrence. There was no statistically significant difference in CDI recurrence rate between the vancomycin monotherapy group and combination
CLOSTRIDIUM DIFFICLE RECURRENCE
139 Table 1. Patient Characteristics
Characteristics
Age, yrs, median (IQR) Age 65 yrs, n (%) Male, n (%) Caucasian, n (%) Transplanted organ, n (%) Kidney Liver Pancreas Simultaneous pancreas and kidney Heart Lung Intestine Time between transplantation and first CDI in days, median (IQR) First CDI 1 year from transplantation, n (%) Delayed graft function, n (%) Organ rejection, n (%) Comorbidities, n (%) Diabetes mellitus Chronic kidney disease Whipple procedure/bypass/Crohn’s disease On dialysis, n (%) NAP1/B1/027 Clostridium difficile strain, n (%) Reinfection History of CDI 8 weeks before index CDI, N (%) CDI severity, n (%) Mild-moderate Severe WBC (cell/mL), median (IQR) Leukopenia, n (%) SCr (mg/dL), mean SD Antibiotic use during 8-week follow-up, n (%) 3rd/4th Generation cephalosporins Carbapenems Trimethoprim/sulfamethoxazole b-lactam/b-lactamase inhibitors Fluoroquinolones Clindamycin Azole antifungals Immunosuppressant therapy during 8-week follow-up, n (%) 1 Immunosuppressant agent 2 Immunosuppressant agents 3 Immunosuppressant agents Steroid Tacrolimus Mycophenolic acid Cyclosporine Gastric acid drugs use after CDI therapy, n (%) Proton pump inhibitors H2-receptor antagonists CDI therapy duration in days, median (IQR)
Oral Vancomycin Monotherapy (N ¼ 35)
57 10 15 25
(43 to 66) (29) (43) (71)
14 4 0 4 7 6 0 1437 25 3 2
(40) (11)
17 12 3 9 5 2 3
Combination Therapy (N ¼ 26)
60 9 17 18
(49 to 67) (35) (65) (69)
P Value
.393 .614 .081 .852
15 4 1 4 3 0 1 447 14 3 0
(58) (15) (3.8) (15) (12)
(49) (34) (8.6) (26) (14) (6) (8.6)
12 10 1 9 3 1 6
(46) (39) (3.8) (35) (12) (4) (23)
21 14 7.2 4 1.4
(60) (40) (5.7 to 12.1) (11) (1.0 to 1.9)
15 11 9.1 5 1.8
(58) (42) (5.3 to 16) (19) (1.1 to 2.2)
3 4 8 4 2 0 18
(8.6) (11) (23) (11) (5.7)
(31) (3.8) (42) (3.8) (7.7)
(51)
8 1 11 1 2 0 17
(65)
.042 .382 .105 .382 1.000 NA .276
(29) (69) (89) (86) (69) (8.6)
4 8 13 19 19 15 4
(15) (31) (50) (73) (73) (58) (15)
.029 .852 .142 .179 .219 .283 .446
0 10 24 31 30 24 3
(11) (20) (17) (294 to 2784) (71) (8.6) (5.7)
21 (60) 12 (34) 16 (15 to 27)
(3.8) (9 to 3372) (54) (8.6)
8 (31) 15 (58) 17 (15 to 23)
.171 .713 .426 .713 .494 .033 .426 .133 .157 1.000 .503 .852 .737 .629 .451 1.000 .739 .152 .856 .856 .599 .477 .357
.024 .069 .774
Abbreviations: IQR, interquartile range; CDI, Clostridium difficile infection; WBC, white blood cell counts; SCr, serum creatinine clearance.
therapy group (22.9% versus 26.9%, respectively; P ¼ .715) nor in time between the end of index CDI therapy and CDI recurrence (27 versus 21 days, respectively; P ¼ .643). After adjusting for NAP1/B1/027 Clostridium difficile strain, choice of CDI therapy, antimicrobial therapy received after end of CDI therapy (cephalosporins, carbapenems, b-lactam/b-
lactams inhibitors, fluoroquinolones, or triazole antifungals), proton pump inhibitors use, liver transplantation, history of diabetes mellitus, and severity of CDI in multivariable logistic regression, the adjusted odds of CDI recurrence did not differ significantly between the two study groups (adjusted odds ratio [OR] ¼ 1.927; 95% confidence interval [CI]: 0.057
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KORAYEM, ELJAALY, MATTHIAS ET AL Table 2. Study Endpoints Study Endpoints
CDI recurrence, n (%) Time between end of CDI therapy and recurrence in days, median (IQR) Total length of hospitalization in days, median (IQR) Length of hospitalization after CDI diagnosis in days, median (IQR)
Oral Vancomycin Monotherapy (N ¼ 35)
8 27 9 4
(23) (9 to 46) (5 to 19) (3 to 9)
Combination Therapy (N ¼ 26)
7 21 14 10
(27) (15 to 22) (6 to 23) (6 to 22)
P Value
.715 .643 .047 .214
Abbreviations: CDI, Clostridium difficile infection; IQR, interquartile range.
to 64.929; P ¼ .715). This model was statistically significant (c2: 47.141; df: 13; N ¼ 61; P < .001) and the good fit was indicated by a lack of statistical significance in the HosmerLomeshow goodness of fit test (P ¼ 1.000). Of the 15 patients who experienced CDI recurrence, 3 (20%) were infected with a different NAP1/B1/027 strain status, whereas 4 had relapse with the same strain. Of these 3, 2 did not have this strain initially but had it in the CDI recurrent episode, whereas 1 had it during the index CDI episode but not during the recurrent CDI episode. A statistically significant difference was found for median total length of hospitalization between the vancomycin monotherapy and combination therapy groups (9 versus 14 days, respectively; P ¼ .047) but not for the median length of hospitalization after CDI diagnosis (8 versus 5 days; respectively; P ¼ .214). DISCUSSION
CDI recurrence remains a significant problem for SOT patients. The rate of CDI recurrence found in this study (25%) is similar to rates previously reported in the SOT population [8e11]. A meta-analysis that pooled data from eight retrospective studies (804 patients) did not find a significant difference in the rate of CDI recurrence between monotherapy and combination therapy for mild CDI (OR: 0.91; 95% CI: 0.66 to 1.26; P ¼ .56) [16]. In agreement with our results, one of the retrospective studies included in this meta-analysis compared oral vancomycin versus combination therapy for severe uncomplicated CDI and found no statistically significant difference in recurrence (4.7% versus 5.7%, respectively; P ¼ 1.0000) [17]. However, it remains questionable if these findings can be extrapolated to the SOT population. Patients with SOT may be at higher risk of recurrence due to post-transplantation hypogammaglobulinemia and compromised immunity [8]. In this study, at least 20% of recurrent CDIs were reinfections caused by another Clostridium difficile strain. A retrospective study including patients with hematological malignancies along with patients who received hematopoietic stem cell transplantation also found numerical but not statistically significant differences in CDI recurrence rates between vancomycin monotherapy, metronidazole monotherapy, and combination therapy (0%, 18.5%, and 38.5%, respectively; P ¼ .140) for treatment of mildmoderate and severe CDI [6]. Most CDI occurrence in patients after SOT has been reported within the first month after transplantation [11,18]. Most previously reported recurrences occurred within 40
days of the initial CDI in kidney and simultaneous pancreaskidney transplant recipients [11]. However, the median time from transplantation to index CDI in our study was considerably longer (968 days), with 64% of patients having their index CDI episode 1 year after transplantation. This may be due to immunosuppressive therapies, persistent disruption of the normal colonic flora, prolonged antimicrobial treatment, and acid suppression therapy. More than half of the patients (59%) in our study were classified as having mild-to-moderate CDI. However, these patients may have been misclassified because current available CDI treatment guideline definitions principally depend on elevated WBC, protein loss, and an increase in premorbid SCr level [12,13]; these criteria may be difficult to apply to SOT recipients who may have existing elevated SCr, who may be receiving dialysis, have a low albumin concentrations at baseline, or who may be neutropenic due to immunosuppressive or prophylactic medications. Data supporting leukopenia (defined as WBC count <1000 cells/mm3) as a risk factor for CDI in SOT recipients is limited, but leukopenia has been linked to the higher rate of intra-abdominal infections in neutropenic patients [19]. Therefore, revising the criteria for assessing CDI severity may be needed in the SOT population, as has been previously suggested for patients with hematologic malignancies [6]. Length of hospitalization was found to be a predictor of a second CDI recurrence in previous studies [15]. CDI has been associated with a median hospital stay of 9.6 days in SOT patients compared to 4 days in non-SOT patients (P < .001) [20]. This cohort found no significant difference in the length of hospitalization after index CDI diagnosis, but total hospitalization was significantly longer in the vancomycin monotherapy group. In hospitalized patients with severe infections, systemic antibiotics may increase length of hospital stay. In those patients, clinicians commonly continue oral vancomycin even after completion of CDI treatment course as CDI prophylaxis while on systemic antibiotics. This practice may partially explain the prolonged hospitalization reported in the vancomycin group in this study. To our knowledge, this is the first study to compare oral vancomycin monotherapy and vancomycin/metronidazole combination therapy for the treatment of uncomplicated CDI in the SOT population. It was clear that the lack of guideline recommendations for CDI antibiotic selection and complexity of this specific population, led clinicians to use different approaches for treatment. One limitation of this
CLOSTRIDIUM DIFFICLE RECURRENCE
study is its retrospective cohort design, which limits data availability and analysis. In addition, although polymerase chain reaction testing in our institution provided Clostridium difficile stain typing information to help distinguish relapse from reinfection, this method for Clostridium difficile toxin detection may be too sensitive and it may have led to the overestimation of index CDI cases, as it is may be unable to differentiate colonization from infection in some patients. However, only patients with at least 3 recorded stools per day initially were included in this study rather than only a positive Clostridium difficile test, but some patients may have had increased stool output for an alternative reason. Lastly, CDI recurrences may not have been captured if they were treated outside of our health network. Given the limitations of our study and lack of other studies, larger prospective studies are necessary to compare treatment strategies for CDI recurrence and evaluate other outcomes. In conclusion, this study shows that SOT recipients are at a high risk of CDI recurrence. However, no difference was found between patients with uncomplicated CDI who were treated with oral vancomycin monotherapy versus those treated with the combination therapy of vancomycin and metronidazole. The study result weakens the practice of prescribing combination therapy for uncomplicated CDI in SOT recipients. Further studies on diagnostic and therapeutic strategies with a focus on SOT recipients are needed to further improve patient outcomes.
REFERENCES [1] Lessa FC, Mu Y, Bamberg WM, et al. Burden of Clostridium difficile infection in the United States. N Engl J Med 2015;372(9): 825e34. [2] Redelings MD, Sorvillo F, Mascola L. Increase in Clostridium difficileerelated mortality rates, United States, 1999e2004. Emerg Infect Dis 2007;13(9):1417e9. [3] Kelly CP, LaMont JT. Clostridium difficile: more difficult than ever. N Engl J Med 2008;359(18):1932e40. [4] Shah SA, Tsapepas DS, Kubin CJ, et al. Risk factors associated with Clostridium difficile infection after kidney and pancreas transplantation. Transpl Infect Dis 2013;15(5):502e9. [5] Kelly CP. Can we identify patients at high risk of recurrent Clostridium difficile infection? Clin Microbiol Infect 2012;18(6):21e7. [6] Zafrani L, Truffaut L, Kreis H, et al. Incidence, risk factors and clinical consequences of neutropenia following kidney transplantation: a retrospective study. Am J Transplant 2009;9(8):1816e25. [7] Kyne L, Warny M, Qamar A, Kelly CP. Asymptomatic carriage of Clostridium difficile and serum levels of IgG antibody against toxin A. N Engl J Med 2000;342(6):390e7.
141 [8] Muñoz P, Giannella M, Alcalá L, et al. Clostridium difficileeassociated diarrhea in heart transplant recipients: is hypogammaglobulinemia the answer? J Heart Lung Transplant 2007;26(9):907e14. [9] Paudel S, Zacharioudakis IM, Zervou FN, Ziakas PD, Mylonakis E. Prevalence of Clostridium difficile infection among solid organ transplant recipients: a meta-analysis of published studies. PLoS One 2015;10(4):e0124483. [10] Lee JT, Kelly RF, Hertz MI, Dunitz JM, Shumway SJ. Clostridium difficile infection increases mortality risk in lung transplant recipients. J Heart Lung Transplant 2013;32(10):1020e6. [11] Keven K, Basu A, Re L, et al. Clostridium difficile colitis in patients after kidney and pancreasekidney transplantation. Transpl Infect Dis 2004;6(1):10e4. [12] Cohen SH, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol 2010;31(05):431e55. [13] Surawicz CM, Brandt LJ, Binion DG, Ananthakrishnan AN, Curry SR, Gilligan PH, et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol 2013;108(4):478e98. [14] Debast SB, Bauer MP, Kuijper EJ, European Society of Clinical Microbiology and Infectious Diseases. European Society of Clinical Microbiology and Infectious Diseases: update of the treatment guidance document for Clostridium difficile infection. Clin Microbiol Infect 2014;20:1e26. [15] Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)da metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009;42:377e81. [16] Li R, Lu L, Lin Y, Wang M, Liu X. Efficacy and safety of metronidazole monotherapy versus vancomycin monotherapy or combination therapy in patients with Clostridium difficile infection: a systematic review and meta-analysis. PLoS One 2015;10(10): e0137252. [17] Bass SN, Bauer SR, Neuner EA, Lam SW. Comparison of treatment outcomes with vancomycin alone versus combination therapy in severe Clostridium difficile infection. J Hosp Infect 2013;85(1):22e7. [18] Parmar SR, Bhatt V, Yang J, Zhang Q, Schuster M. A retrospective review of metronidazole and vancomycin in the management of Clostridium difficile infection in patients with hematologic malignancies. J Oncol Pharm Pract 2014;20(3): 172e82. [19] Pant C, Anderson MP, O’connor JA, Marshall CM, Deshpande A, Sferra TJ. Association of Clostridium difficile infection with outcomes of hospitalized solid organ transplant recipients: results from the 2009 Nationwide Inpatient Sample database. Transpl Infect Dis 2012;14(5):540e7. [20] Boutros M, Al-Shaibi M, Chan G, et al. Clostridium difficile colitis: increasing incidence, risk factors, and outcomes in solid organ transplant recipients. Transplantation 2012;93(10): 1051e7.
ABSTRACT Introduction. Solid organ transplant (SOT) recipients are at high risk of Clostridium difficile infection (CDI) and CDI recurrence due to their suppressed immune systems and antibiotic exposure. A combination of metronidazole and oral vancomycin is often prescribed for SOT recipients with uncomplicated CDI despite any clinical practice guidelines supporting the need for combination therapy. This study aims to compare the CDI recurrence rates of metronidazole/vancomycin combination therapy to oral vancomycin monotherapy in SOT recipients after a first episode of uncomplicated CDI. Methods. A single-center retrospective cohort study evaluated SOT recipients diagnosed with uncomplicated CDI who were treated with vancomycin monotherapy or vancomycin/ metronidazole combination therapy. The primary endpoint was CDI recurrence defined as a second CDI episode within 8 weeks of completing index CDI therapy. The secondary endpoints were time between the end of CDI therapy and recurrence, length of total hospitalization after the index CDI, and length of hospitalization after index CDI diagnosis. Results. Fifteen patients (25%) of 61 subjects experienced CDI recurrence. There was no statistically significant difference in CDI recurrence rate between the vancomycin monotherapy group and combination therapy group (23% versus 27%, respectively; P ¼ .715). The median total length of hospitalization between the vancomycin monotherapy and combination therapy groups was statistically significant (9 versus 14 days, respectively; P ¼ .047). Discussion. There was no difference found in recurrence rate between oral vancomycin monotherapy versus combination therapy. The study result weakens the practice of prescribing combination therapy for uncomplicated CDI in SOT recipients.
C
LOSTRIDIUM difficile infection (CDI) is a common cause of hospital-acquired infection and is associated with increasing morbidity and mortality [1e3]. Even though most patients with CDI will respond to therapy with either metronidazole, vancomycin (oral), or fidaxomicin, the number of patients with CDI recurrence has dramatically increased over the years [4]. Recurrent CDI can be caused by either relapse due to the original infecting strain or reinfection with a new strain [5]. Solid organ transplant (SOT) recipients are at high risk for CDI recurrence due to suppressed immune systems, prolonged hospitalizations, broad-spectrum ª 2017 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, 50, 137e141 (2018)
antimicrobial use, leukopenia, post-transplantation hypogammaglobulinemia, polyclonal antibodies induction therapy, and high-dose corticosteroid use [6e8]. The reported rate of CDI recurrence in patients after SOT ranges from 8.5% to 40%, which is higher than the reported rate of 10 to 20% in the general population [8e11].
*Address correspondence to Ghazwa B. Korayem, PharmD, University of Arizona, 1295 N. Martin, PO Box 210202, Tucson, Arizona. E-mail: [email protected] 0041-1345/17 https://doi.org/10.1016/j.transproceed.2017.11.016
137
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Although metronidazole is the first-line agent for treatment of mild-to-moderate CDI [12], metronidazole monotherapy is often not prescribed by clinicians due to their consideration of the interaction between tacrolimus and metronidazole in patients with SOT. Instead, the combination of metronidazole and oral vancomycin is often prescribed for SOT patients and other perceived fragile or immunocompromised patients with uncomplicated CDI, despite any clinical practice guidelines supporting combination therapy in this population [12e14]. Whereas this combination therapy is currently recommended only for complicated, severe CDI with ileus, this tendency is likely due to clinicians’ hesitation to follow guidelines that do not specifically address how to treat SOT recipients [12,13]. Because SOT is a common exclusion criterion in studies comparing CDI treatment regimens, there are limited published data regarding treatment of CDI in this population. Recurrence rate is one of the major outcomes that should be assessed when evaluating antibiotics used for CDI therapy. Therefore, this study aims to compare the CDI recurrence rates of metronidazole/vancomycin combination therapy to oral vancomycin monotherapy in SOT recipients after the first episode of uncomplicated CDI. PATIENTS AND METHODS Study Design and Patient Population In this retrospective cohort study, institutional review board approval was obtained. CDI recurrence rates were evaluated in SOT recipients who received oral vancomycin monotherapy or a combination of vancomycin/metronidazole for an initial CDI episode. The attending physician determined CDI treatment and duration while the patient was admitted to a tertiary care, academic medical center between November 1, 2013, and October 30, 2016. Patients were followed for 8 weeks after completion of CDI therapy to assess CDI recurrence. Exclusion criteria included <18 years of age, if another CDI occurred within 8 weeks before study period, hematopoietic stem cell transplantation or use of fecal microbiota transplantation, metronidazole monotherapy, and use of fidaxomicin or rifaximin during initial CDI therapy. Patients who met the Society for Healthcare Epidemiology of America’s (SHEA) and Infectious Diseases Society of America (IDSA) criteria for severe and complicated CDI [12], experienced treatment cross-over, or died within the follow-up period (8 weeks) were also excluded.
Endpoints and Definitions The primary endpoint of CDI recurrence was defined as experiencing a second CDI episode within 8 weeks of completing index CDI therapy [13]. A CDI episode was defined as having both 3 loose stools per day and microbiological evidence of the Clostridium difficile toxin isolate by enzyme-linked immunosorbent assay or polymerase chain reaction testing. The secondary endpoints were time between the end of CDI therapy and recurrence, length of total hospitalization after the index CDI, and length of hospitalization after index CDI diagnosis. CDI disease severity definitions and therapy recommendations were based on SHEA and IDSA guidelines [12]. Mild-moderate CDI was defined as having a white blood cell (WBC) count of <15,000 cells/mL and serum creatinine level (SCr) of <1.5 times premorbid levels. Severe CDI was defined by either having a WBC 15,000
KORAYEM, ELJAALY, MATTHIAS ET AL cells/mL or SCr >1.5 times premorbid levels. Uncomplicated CDI was defined as not meeting IDSA or American College of Gastroenterology (ACG) criteria for complicated CDI, which include hypotension, shock, ileus, megacolon, significant abdominal distention, colonic perforation, colectomy, intensive care unit admission, fever 38.5 C, mental status changes, WBC 35,000 cells/mm3 or <2000 cells/mm3, serum lactate concentrations >2.2 mmol/L, or end organ failure (mechanical ventilation, renal failure). Patients who received oral vancomycin and metronidazole concomitantly at any point during therapy were considered to be part of the combination group, whereas patients who received oral vancomycin alone without switching between agents “crossover” were considered to be part of the monotherapy group.
Data Analysis All patient charts were reviewed using a standard data collection, and data was entered into a standard electronic data collection form using the web-based application REDCap [15] (REDCAP version 8.1.1 Nashville,TN,USA hosted at University of Arizona). Statistical analyses were performed with SPSS software, version 24 (IBM, Armonk, New York, United States). Non-normally distributed continuous data were described using the median (interquartile range [IQR]), and differences between the study groups were compared using a 2-tailed Mann-Whitney U test. Categorical data were described as counts (%), and a Fisher’s exact or c2 test was used for comparison. We adjusted for confounding variables and used a multivariable logistic regression analysis to assess CDI recurrence. If a variable was considered clinically relevant or its P value was <.2, that variable was considered for the regression analysis.
RESULTS
During the initial screening of 94 patients, patients were excluded for the following reasons: complicated CDI (n ¼ 3), recurrent CDI with initial CDI before study period (n ¼ 1), death unrelated to CDI during the follow-up period (n ¼ 2), initial treatment crossover (n ¼ 6), and receiving metronidazole (n ¼ 21). This left a final total of 61 patients, with 35 in the oral vancomycin monotherapy arm and 26 in the combination vancomycin/metronidazole therapy arm. The demographic and baseline characteristics of these patients are described in Table 1. There were no statistically significant differences between the two study groups, except patients in the vancomycin monotherapy arm were more likely to have underwent lung transplantation or received proton-pump inhibitors after CDI therapy and less likely to have received third/fourth generation cephalosporins during the 8-week follow-up period. The median age of patients was 60 years and the proportion of patients 64 years of age was approximately 30%. The most common type of organ transplantation was kidney, which was found in half of the patients. The ratio of having mild-moderate CDI to severe CDI was 3:2. The NAP1/B1/027 strain of Clostridium difficile was found in 13% of patients. The median CDI antibiotic therapy duration was 16 days. The study outcomes are presented in Table 2. Fifteen patients (25%) experienced CDI recurrence. There was no statistically significant difference in CDI recurrence rate between the vancomycin monotherapy group and combination
CLOSTRIDIUM DIFFICLE RECURRENCE
139 Table 1. Patient Characteristics
Characteristics
Age, yrs, median (IQR) Age 65 yrs, n (%) Male, n (%) Caucasian, n (%) Transplanted organ, n (%) Kidney Liver Pancreas Simultaneous pancreas and kidney Heart Lung Intestine Time between transplantation and first CDI in days, median (IQR) First CDI 1 year from transplantation, n (%) Delayed graft function, n (%) Organ rejection, n (%) Comorbidities, n (%) Diabetes mellitus Chronic kidney disease Whipple procedure/bypass/Crohn’s disease On dialysis, n (%) NAP1/B1/027 Clostridium difficile strain, n (%) Reinfection History of CDI 8 weeks before index CDI, N (%) CDI severity, n (%) Mild-moderate Severe WBC (cell/mL), median (IQR) Leukopenia, n (%) SCr (mg/dL), mean SD Antibiotic use during 8-week follow-up, n (%) 3rd/4th Generation cephalosporins Carbapenems Trimethoprim/sulfamethoxazole b-lactam/b-lactamase inhibitors Fluoroquinolones Clindamycin Azole antifungals Immunosuppressant therapy during 8-week follow-up, n (%) 1 Immunosuppressant agent 2 Immunosuppressant agents 3 Immunosuppressant agents Steroid Tacrolimus Mycophenolic acid Cyclosporine Gastric acid drugs use after CDI therapy, n (%) Proton pump inhibitors H2-receptor antagonists CDI therapy duration in days, median (IQR)
Oral Vancomycin Monotherapy (N ¼ 35)
57 10 15 25
(43 to 66) (29) (43) (71)
14 4 0 4 7 6 0 1437 25 3 2
(40) (11)
17 12 3 9 5 2 3
Combination Therapy (N ¼ 26)
60 9 17 18
(49 to 67) (35) (65) (69)
P Value
.393 .614 .081 .852
15 4 1 4 3 0 1 447 14 3 0
(58) (15) (3.8) (15) (12)
(49) (34) (8.6) (26) (14) (6) (8.6)
12 10 1 9 3 1 6
(46) (39) (3.8) (35) (12) (4) (23)
21 14 7.2 4 1.4
(60) (40) (5.7 to 12.1) (11) (1.0 to 1.9)
15 11 9.1 5 1.8
(58) (42) (5.3 to 16) (19) (1.1 to 2.2)
3 4 8 4 2 0 18
(8.6) (11) (23) (11) (5.7)
(31) (3.8) (42) (3.8) (7.7)
(51)
8 1 11 1 2 0 17
(65)
.042 .382 .105 .382 1.000 NA .276
(29) (69) (89) (86) (69) (8.6)
4 8 13 19 19 15 4
(15) (31) (50) (73) (73) (58) (15)
.029 .852 .142 .179 .219 .283 .446
0 10 24 31 30 24 3
(11) (20) (17) (294 to 2784) (71) (8.6) (5.7)
21 (60) 12 (34) 16 (15 to 27)
(3.8) (9 to 3372) (54) (8.6)
8 (31) 15 (58) 17 (15 to 23)
.171 .713 .426 .713 .494 .033 .426 .133 .157 1.000 .503 .852 .737 .629 .451 1.000 .739 .152 .856 .856 .599 .477 .357
.024 .069 .774
Abbreviations: IQR, interquartile range; CDI, Clostridium difficile infection; WBC, white blood cell counts; SCr, serum creatinine clearance.
therapy group (22.9% versus 26.9%, respectively; P ¼ .715) nor in time between the end of index CDI therapy and CDI recurrence (27 versus 21 days, respectively; P ¼ .643). After adjusting for NAP1/B1/027 Clostridium difficile strain, choice of CDI therapy, antimicrobial therapy received after end of CDI therapy (cephalosporins, carbapenems, b-lactam/b-
lactams inhibitors, fluoroquinolones, or triazole antifungals), proton pump inhibitors use, liver transplantation, history of diabetes mellitus, and severity of CDI in multivariable logistic regression, the adjusted odds of CDI recurrence did not differ significantly between the two study groups (adjusted odds ratio [OR] ¼ 1.927; 95% confidence interval [CI]: 0.057
140
KORAYEM, ELJAALY, MATTHIAS ET AL Table 2. Study Endpoints Study Endpoints
CDI recurrence, n (%) Time between end of CDI therapy and recurrence in days, median (IQR) Total length of hospitalization in days, median (IQR) Length of hospitalization after CDI diagnosis in days, median (IQR)
Oral Vancomycin Monotherapy (N ¼ 35)
8 27 9 4
(23) (9 to 46) (5 to 19) (3 to 9)
Combination Therapy (N ¼ 26)
7 21 14 10
(27) (15 to 22) (6 to 23) (6 to 22)
P Value
.715 .643 .047 .214
Abbreviations: CDI, Clostridium difficile infection; IQR, interquartile range.
to 64.929; P ¼ .715). This model was statistically significant (c2: 47.141; df: 13; N ¼ 61; P < .001) and the good fit was indicated by a lack of statistical significance in the HosmerLomeshow goodness of fit test (P ¼ 1.000). Of the 15 patients who experienced CDI recurrence, 3 (20%) were infected with a different NAP1/B1/027 strain status, whereas 4 had relapse with the same strain. Of these 3, 2 did not have this strain initially but had it in the CDI recurrent episode, whereas 1 had it during the index CDI episode but not during the recurrent CDI episode. A statistically significant difference was found for median total length of hospitalization between the vancomycin monotherapy and combination therapy groups (9 versus 14 days, respectively; P ¼ .047) but not for the median length of hospitalization after CDI diagnosis (8 versus 5 days; respectively; P ¼ .214). DISCUSSION
CDI recurrence remains a significant problem for SOT patients. The rate of CDI recurrence found in this study (25%) is similar to rates previously reported in the SOT population [8e11]. A meta-analysis that pooled data from eight retrospective studies (804 patients) did not find a significant difference in the rate of CDI recurrence between monotherapy and combination therapy for mild CDI (OR: 0.91; 95% CI: 0.66 to 1.26; P ¼ .56) [16]. In agreement with our results, one of the retrospective studies included in this meta-analysis compared oral vancomycin versus combination therapy for severe uncomplicated CDI and found no statistically significant difference in recurrence (4.7% versus 5.7%, respectively; P ¼ 1.0000) [17]. However, it remains questionable if these findings can be extrapolated to the SOT population. Patients with SOT may be at higher risk of recurrence due to post-transplantation hypogammaglobulinemia and compromised immunity [8]. In this study, at least 20% of recurrent CDIs were reinfections caused by another Clostridium difficile strain. A retrospective study including patients with hematological malignancies along with patients who received hematopoietic stem cell transplantation also found numerical but not statistically significant differences in CDI recurrence rates between vancomycin monotherapy, metronidazole monotherapy, and combination therapy (0%, 18.5%, and 38.5%, respectively; P ¼ .140) for treatment of mildmoderate and severe CDI [6]. Most CDI occurrence in patients after SOT has been reported within the first month after transplantation [11,18]. Most previously reported recurrences occurred within 40
days of the initial CDI in kidney and simultaneous pancreaskidney transplant recipients [11]. However, the median time from transplantation to index CDI in our study was considerably longer (968 days), with 64% of patients having their index CDI episode 1 year after transplantation. This may be due to immunosuppressive therapies, persistent disruption of the normal colonic flora, prolonged antimicrobial treatment, and acid suppression therapy. More than half of the patients (59%) in our study were classified as having mild-to-moderate CDI. However, these patients may have been misclassified because current available CDI treatment guideline definitions principally depend on elevated WBC, protein loss, and an increase in premorbid SCr level [12,13]; these criteria may be difficult to apply to SOT recipients who may have existing elevated SCr, who may be receiving dialysis, have a low albumin concentrations at baseline, or who may be neutropenic due to immunosuppressive or prophylactic medications. Data supporting leukopenia (defined as WBC count <1000 cells/mm3) as a risk factor for CDI in SOT recipients is limited, but leukopenia has been linked to the higher rate of intra-abdominal infections in neutropenic patients [19]. Therefore, revising the criteria for assessing CDI severity may be needed in the SOT population, as has been previously suggested for patients with hematologic malignancies [6]. Length of hospitalization was found to be a predictor of a second CDI recurrence in previous studies [15]. CDI has been associated with a median hospital stay of 9.6 days in SOT patients compared to 4 days in non-SOT patients (P < .001) [20]. This cohort found no significant difference in the length of hospitalization after index CDI diagnosis, but total hospitalization was significantly longer in the vancomycin monotherapy group. In hospitalized patients with severe infections, systemic antibiotics may increase length of hospital stay. In those patients, clinicians commonly continue oral vancomycin even after completion of CDI treatment course as CDI prophylaxis while on systemic antibiotics. This practice may partially explain the prolonged hospitalization reported in the vancomycin group in this study. To our knowledge, this is the first study to compare oral vancomycin monotherapy and vancomycin/metronidazole combination therapy for the treatment of uncomplicated CDI in the SOT population. It was clear that the lack of guideline recommendations for CDI antibiotic selection and complexity of this specific population, led clinicians to use different approaches for treatment. One limitation of this
CLOSTRIDIUM DIFFICLE RECURRENCE
study is its retrospective cohort design, which limits data availability and analysis. In addition, although polymerase chain reaction testing in our institution provided Clostridium difficile stain typing information to help distinguish relapse from reinfection, this method for Clostridium difficile toxin detection may be too sensitive and it may have led to the overestimation of index CDI cases, as it is may be unable to differentiate colonization from infection in some patients. However, only patients with at least 3 recorded stools per day initially were included in this study rather than only a positive Clostridium difficile test, but some patients may have had increased stool output for an alternative reason. Lastly, CDI recurrences may not have been captured if they were treated outside of our health network. Given the limitations of our study and lack of other studies, larger prospective studies are necessary to compare treatment strategies for CDI recurrence and evaluate other outcomes. In conclusion, this study shows that SOT recipients are at a high risk of CDI recurrence. However, no difference was found between patients with uncomplicated CDI who were treated with oral vancomycin monotherapy versus those treated with the combination therapy of vancomycin and metronidazole. The study result weakens the practice of prescribing combination therapy for uncomplicated CDI in SOT recipients. Further studies on diagnostic and therapeutic strategies with a focus on SOT recipients are needed to further improve patient outcomes.
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141 [8] Muñoz P, Giannella M, Alcalá L, et al. Clostridium difficileeassociated diarrhea in heart transplant recipients: is hypogammaglobulinemia the answer? J Heart Lung Transplant 2007;26(9):907e14. [9] Paudel S, Zacharioudakis IM, Zervou FN, Ziakas PD, Mylonakis E. Prevalence of Clostridium difficile infection among solid organ transplant recipients: a meta-analysis of published studies. PLoS One 2015;10(4):e0124483. [10] Lee JT, Kelly RF, Hertz MI, Dunitz JM, Shumway SJ. Clostridium difficile infection increases mortality risk in lung transplant recipients. J Heart Lung Transplant 2013;32(10):1020e6. [11] Keven K, Basu A, Re L, et al. Clostridium difficile colitis in patients after kidney and pancreasekidney transplantation. Transpl Infect Dis 2004;6(1):10e4. [12] Cohen SH, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol 2010;31(05):431e55. [13] Surawicz CM, Brandt LJ, Binion DG, Ananthakrishnan AN, Curry SR, Gilligan PH, et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol 2013;108(4):478e98. [14] Debast SB, Bauer MP, Kuijper EJ, European Society of Clinical Microbiology and Infectious Diseases. European Society of Clinical Microbiology and Infectious Diseases: update of the treatment guidance document for Clostridium difficile infection. Clin Microbiol Infect 2014;20:1e26. [15] Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)da metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009;42:377e81. [16] Li R, Lu L, Lin Y, Wang M, Liu X. Efficacy and safety of metronidazole monotherapy versus vancomycin monotherapy or combination therapy in patients with Clostridium difficile infection: a systematic review and meta-analysis. PLoS One 2015;10(10): e0137252. [17] Bass SN, Bauer SR, Neuner EA, Lam SW. Comparison of treatment outcomes with vancomycin alone versus combination therapy in severe Clostridium difficile infection. J Hosp Infect 2013;85(1):22e7. [18] Parmar SR, Bhatt V, Yang J, Zhang Q, Schuster M. A retrospective review of metronidazole and vancomycin in the management of Clostridium difficile infection in patients with hematologic malignancies. J Oncol Pharm Pract 2014;20(3): 172e82. [19] Pant C, Anderson MP, O’connor JA, Marshall CM, Deshpande A, Sferra TJ. Association of Clostridium difficile infection with outcomes of hospitalized solid organ transplant recipients: results from the 2009 Nationwide Inpatient Sample database. Transpl Infect Dis 2012;14(5):540e7. [20] Boutros M, Al-Shaibi M, Chan G, et al. Clostridium difficile colitis: increasing incidence, risk factors, and outcomes in solid organ transplant recipients. Transplantation 2012;93(10): 1051e7.