Exploring failure of antimicrobial prophylaxis and pre-emptive therapy for transplant recipients: a systematic review

Objectives Infections remain a threat for solid organ and stem cell transplant recipients. Antimicrobial prophylaxis and pre-emptive therapy have improved survival of these patients; however, the failure rates of prophylaxis are not negligible. The aim of this systematic review is to explore the reasons behind failure of antimicrobial prophylaxis and pre-emptive therapy. Setting This systematic review included prospective randomised controlled trials and prospective single-arm studies. Participants The studies included were on prophylaxis and pre-emptive therapy of opportunistic infections in transplant recipients. Studies were included from databases MEDLINE, CENTRAL and Embase published until October first 2018. Primary and secondary outcome measures Primary outcome measures were breakthrough infections, adverse events leading to stopping of treatment, switching medication or dose reduction. Secondary outcome measures were acquired resistance to antimicrobials, antifungals or antivirals and death. Results From 3317 identified records, 30 records from 24 studies with 2851 patients were included in the systematic review. Seventeen focused on prophylactic and pre-emptive treatment of cytomegalovirus and seven studies on invasive fungal infection. The main reasons for failure of prophylaxis and pre-emptive therapy were adverse events and breakthrough infections, which were described in 54% (13 studies) and 38% (9 studies) of the included studies, respectively. In 25%, six of the studies, a detailed description of patients who experienced failure of prophylaxis or pre-emptive therapy was unclear or lacking. Conclusions Our results show that although failure is reported in the studies, the level of detail prohibits a detailed analysis of failure of prophylaxis and pre-emptive therapy. Clearly reporting on patients with a negative outcome should be improved. We have provided guidance on how to detect failure early in a clinical setting in accordance to the results from this systematic review. PROSPERO registration number CRD42017077606.


GENERAL COMMENTS
I applaud the authors for their interesting question. Attempts to glean and assess more granular details related to breakthrough and adverse drug events in these studies are warranted. Though these data reporting gaps are a known phenomenon in the literature, you have specifically highlighted the data gaps present in trials done in stem cell and solid organ transplant recipients.
However there was not enough data reported in these trials to perform the intended analysis. I am not clear that the results address the primary and secondary research questions or objectives. the goal was to explore failures of antimicrobial prophylaxis and pre-emtive therapy -this was unable to be done given absence of data. Additionally, if a true systematic review is to be done, then why were no retrospective studies included? Additionally there is little to no mention of the findings or results related to resistance to antimicrobials, antifungals, or antivirals. Because specific data was not present it appears the focus of the manuscript shifted to a focus on absence of data and then a recommendation of how to detect failure early in a clinical setting. Again, this focus does not seem to answer the primary or secondary outcome. Another limitation is heterogeneity of populations and adverse drug events and breakthrough. Combining stem cell and solid organ transplant populations is problematic as they both experience different common complications (for instance GVHD, or surgical complications) and different drug-drug interactions. Also different drugs were evaluated that have very different spectra and known side effect profiles.
Overall the manuscript is not focused and could be improved by better defining the goals and objectives and tying those more clearly to the results. For completeness I would also recommend evaluating retrospective studies if goal is systematic review.

Martin Howell
University of Sydney Australia REVIEW RETURNED 11-Nov-2019

GENERAL COMMENTS
This systematic review addresses two important aspects. Firstly the subject of the review is a clinically important question to address. Secondly the review highlights the problems arising with inadequate reporting of harms in clinical trials. I have some comments to make that I hope might improve the manuscript.
1. The methods section should provide justification for the start date of 2010. 2. In the discussion section it is stated we therefore believe that: 'adding studies on children would have made it more difficult to summarize findings.' This is not a valid reason for not including children, particularly as the number of included studies is quite small. Children could have been addressed separately. Irrespective this should be addressed in the methods section not discussion.
3. Figures 2 and 3 show the number of participants. This should be shown as proportions of each of the transplant groups given the variation in total numbers across the groups. This is a particular problem as it is hard for the reader to find this number. To that end it would be useful either in the text or a summary table to give the split between transplant groups. As an example the 'other' numbers for kidney transplants are high, however the proportions may be similar, higher or lower when compared to the other groups. Other is problematic for the reason noted by the authors. 4. Given the above, suggested that 'other' be included in Table 2. 5. Table 2 is difficult to read. I suggest it be restructured to with reasons for stopping as columns. In addition the table should include total number for each trial and include proportions as well as n e.g. ## (##%). It is also unclear from table 2 where particular AEs have been specified and where they have not. Does the absence of brackets mean the AEs are unspecified. Do the inclusions in the brackets when provided refer only to AEs relevant to prophylaxis/pre-emptive treatment? Table 2 could provide more of this information. 6. In my view Table 3 does not provide any useful information and it does not contribute to the overall findings. Indeed only 2 sentences are given over to Table 3  However there was not enough data reported in these trials to perform the intended analysis. I am not clear that the results address the primary and secondary research questions or objectives. the goal was to explore failures of antimicrobial prophylaxis and pre-emtive therapy -this was unable to be done given absence of data. Additionally, if a true systematic review is to be done, then why were no retrospective studies included? Additionally there is little to no mention of the findings or results related to resistance to antimicrobials, antifungals, or antivirals. Because specific data was not present it appears the focus of the manuscript shifted to a focus on absence of data and then a recommendation of how to detect failure early in a clinical setting. Again, this focus does not seem to answer the primary or secondary outcome. Another limitation is heterogeneity of populations and adverse drug events and breakthrough. Combining stem cell and solid organ transplant populations is problematic as they both experience different common complications (for instance GVHD, or surgical complications) and different drug-drug interactions. Also different drugs were evaluated that have very different spectra and known side effect profiles.
Overall the manuscript is not focused and could be improved by better defining the goals and objectives and tying those more clearly to the results. For completeness I would also recommend evaluating retrospective studies if goal is systematic review.  We defined the primary and secondary outcomes for this review beforehand to provide transparency and documented this in a protocol, which we uploaded to PROSPERO. The secondary outcome resistance to antimicrobials, antivirals and antifungals was usually addressed in the introductions and discussions of the included studies, however not regarded as failure of therapy. Palmer et al 2010 and Boeckh et al 2015 (Table 1) both report on measurement of resistance, however in the study by Boeckh and colleagues no resistance was confirmed and Palmer and colleagues mention one known resistance mutation. Because a majority of all studies did not report on resistance and did not connect this to the failure of prophylaxis and/or pre-emptive therapy we did not include this in the review. The other secondary outcome, death we have reported in Table 2, however for clarity we have included a short section on this in the results section.
Revised section in results: From the secondary outcomes death was reported more frequentlyin 33% (n=8) of the studies death was the reason for failure 17,27,30,31,35,36,44,46 . The secondary outcome resistance to antimicrobials, antivirals and antifungals was addressed in the introductions and discussions of the included studies, however not regarded as failure of therapy. Moreover, the presence and/or measurement of resistance to the study drug was described in 2 studies 27,29 . Boeckh et al report no resistance genes in the investigated patients and Palmer et al report one patient with known resistance to ganciclovir.
 We included a wide population and different antimicrobials to see overview in different infectious diseases where routine prophylaxis and/or pre-emptive therapy is used, often for an extended period. As this is a burden for healthcare and as mentioned in our introduction and discussionoften not supported by new evidence, we believed that we could find patterns that could improve prophylaxis and/or pre-emptive therapy in the wider patient population. As mentioned before, we have included some objectives in the introduction.

Revised section in the introduction:
This systematic review will identify 1) causes of failure of prophylactic treatment, 2) factors that might contribute to failure of prophylaxis and 3) different approaches for administering prophylaxis.
This systematic review aimed to summarize the main reasons why prophylaxis and pre-emptive therapy has failed in solid organ and allogeneic stem cell transplant recipients and how failure is reported in prospective studies. In this review we focus on failure of prophylactic therapy, during the treatment window.
Reviewer: 2 Reviewer Name: Martin Howell Institution and Country: University of Sydney, Australia Please state any competing interests or state 'None declared': None declared This systematic review addresses two important aspects. Firstly the subject of the review is a clinically important question to address. Secondly the review highlights the problems arising with inadequate reporting of harms in clinical trials. I have some comments to make that I hope might improve the manuscript.
1. The methods section should provide justification for the start date of 2010.
Response to reviewer: We have provided this justification in the discussion section: Furthermore, a limitation of our study was the restriction of start date (1 st January 2010). This was done to avoid the effect of the significant change in management of infections and focus on the most recent evidence 11,12 .
However, we will include a statement also in the methods section.

Revised section in methods:
This systematic review included prospective randomized controlled trials and prospective single-arm studies from January 1 st 2010 to October 1 st 2018. The starting date was January 1 st 2010 due to the changes in management of different infections in recent decades and to include the most recent evidence 11,12 .
2. In the discussion section it is stated we therefore believe that: 'adding studies on children would have made it more difficult to summarize findings.' This is not a valid reason for not including children, particularly as the number of included studies is quite small. Children could have been addressed separately. Irrespective this should be addressed in the methods section not discussion.
Response to reviewer: We agree, that this study could have indeed included children. However, as we already have quite a heterogeneous patient population with multiple infections being investigated, we believe that children introduce even more variability and are not the scope of this review. We have included a statement in the methods section.
Revised section in methods: The review included patients (16 years and older) who had received either allogeneic stem cell, lung, kidney, liver, heart, pancreas or small bowel transplantation. Studies done on children under 16 years were not included as this would have introduced more variability and require a separate analysis, thus were out with the scope of this review.