Lincomycin Administration against Persistent Multi-Drug Resistant Chronic Endometritis in Infertile Women with a History of Repeated Implantation Failure
Round 1
Reviewer 1 Report
Chronic endometritis (CE) is a common cause of implantation failure during IVF procedures, as well as spontaneous miscarriages, even despite the transfer of a euploid embryo into the uterine cavity. The prevalence of CE among infertile patients with repeated implantation failures is approximately 50%. Inflammatory diseases of the pelvic organs (PID), including chronic endometritis, are one of the causes of impaired receptive properties of the endometrium. One of the reasons for discussion is the determination of the role of microorganisms identified in the endometrium in the genesis of chronic inflammation and associated infertility. This problem is in the content of the general theory of chronic inflammation and its consequences for the functional reproductive system. As part of the study of the role of the human microbiome in reproduction, data were obtained on its composition in the endometrium: hysterectomized uterus, PID, infertility, repeated implantation failures, non-developing pregnancy, and conditionally healthy patients. A new paradigm of pregravid strategy has been formed, and this applies, first of all, to empirical antibiotic therapy for PID and chronic endometritis. However, the treatment of chronic endometritis is still controversial, especially since there is antibiotic resistance of the identified microorganisms, especially when conducting several courses of treatment. The authors investigated the efficacy of lincomycin (lincomycin hydrochloride hydrate (Lincocin, 1,500 mg/day for 14 days, Pfizer Inc.) in the treatment of CE in 6 patients with IVF failure who were not responding to oral azithromycin or moxifloxacin therapy.
It should be noted that this is an antibiotic of the lincosamide group, which is quite outdated and does not have a wide spectrum of antimicrobial activity. The effectiveness of this antibiotic is estimated at 19-38%. It is possible that due to the rare use of this antibiotic in clinical practice, the sensitivity of microorganisms to causative agents of CE is still quite high.
Author Response
Thank you for your review and comments on our manuscript.
Please note that Materials and Methods section are rewritten to avoid the duplication of our own previous articles following the direction of the journal editorial office.
Q. It should be noted that this is an antibiotic of the lincosamide group, which is quite outdated and does not have a wide spectrum of antimicrobial activity. The effectiveness of this antibiotic is estimated at 19-38%. It is possible that due to the rare use of this antibiotic in clinical practice, the sensitivity of microorganisms to causative agents of CE is still quite high.
A. As written in the first submission, we discussed that “lincomycin is a narrow spectrum lincosamide antibiotic agent.” (line 223). We added the following sentences in line 190 and 203-5. “The effectiveness of this antibiotic is estimated at 19-38%.” “One possible explanation for the effect of lincomycin on our cases may be due to the rare use of and rather lower resistance against this antibiotic agent in clinical practice.”
Reviewer 2 Report
This manuscript, entitled “Lincomycin Administration against Persistent Multi-drug Resistant Chronic Endometritis in Infertile Women with a History of Repeated Implantation Failure”, has described six cases of persistent MDR-CE in infertile women who were resistant to all the commonly used antibiotic agents. The results suggest Oral lincomycin administration (14-day, 1,500mg/day) was effective in the eradication of ESPCs in these women. Due to some significant drawbacks, my suggestion is rejection.
Firstly, the major disadvantage of this study is the overlook of the strains causing multidrug resistance chronic endometritis. Concerning multidrug resistance, it is of importance to know which exactly the strain(s) is/are and the resistance determinants. However, in the current study, the authors failed to provide any information concerning the strain(s).
Secondly, as the authors mentioned, there are three potential biases in this study. In my opinion, the three biases would cause huge difference and are unacceptable. I strongly suggest the authors to dig more into which strain(s) cause such infection and investigate on the strain(s).
Author Response
Thank you for your review and comments on our manuscript.
Please note that Materials and Methods section are rewritten to avoid the duplication of our own previous articles following the direction of the journal editorial office.
Q. ..... Due to some significant drawbacks, my suggestion is rejection.
Firstly, the major disadvantage of this study is the overlook of the strains causing multidrug resistance chronic endometritis. Concerning multidrug resistance, it is of importance to know which exactly the strain(s) is/are and the resistance determinants. However, in the current study, the authors failed to provide any information concerning the strain(s).
Secondly, as the authors mentioned, there are three potential biases in this study. In my opinion, the three biases would cause huge difference and are unacceptable. I strongly suggest the authors to dig more into which strain(s) cause such infection and investigate the strain(s).
A. Thank you for your reasonable review comments on our manuscript. Yes, you are right. We admit that the choice of lincomycin is not a scientifically-selected one as you suggested that we should have dug into bacterial genera/species that cause multi-drug resistant (MDR)-CE. We will pursue the causative bacteria of MDR-CE in future study.
Reviewer 3 Report
The manuscript by Kitaya et al describes a case report regarding a successful treatment of multi-drug resistant chronic endometriosis with lincomycin in infertility patients, resulting in good patient outcomes (3 out of 5 live births). The results of these case reports are worth reporting. However, the manuscript needs improvements.
- The discussion section is very small. Comparison of results with the literature is mandatory.
- It is not clear why the microbiome studies have failed twice - maybe you could describe your findings?
- line 143: I do not understand why these particular taxa has been excluded from the analysis. A fast literature search has revealed that for instance E. coli can be involved in this medical condition. Probably you need to re-analyse the results.
- Were there swabs/cultures taken at the time of infection? Were the species involved identified? These would help to discuss and support the use of lincomycin.
- The authors briefly mentioned that some women were taking prebiotics/probiotics. This would massively influence treatment outcomes so it should be described in detail.
- Minor suggestion (line 50): the study described here published elsewhere so please add reference
Author Response
Thank you for your review and comments on our manuscript.
Please note that Materials and Methods section are rewritten to avoid the duplication of our own previous articles following the direction of the journal editorial office.
Q. The manuscript by Kitaya et al describes a case report regarding successful treatment of multi-drug resistant chronic endometriosis with lincomycin in infertility patients, resulting in good patient outcomes (3 out of 5 live births). The results of these case reports are worth reporting. However, the manuscript needs improvements.
-The discussion section is very small. Comparison of results with the literature is mandatory.
A. We added the following discussion and references No. 18-19 for comparison with the literature (line 165-170 and reference list): “CE is no exception regarding antibiotic resistance. Cicinelli et al. reported that less than 20% of CE was resistant to single-course oral doxycycline treatment in 2008, but 24.6% of CE was untreatable with three courses of antibiotic administration (2, 18). More recently, Xiong et al. reported that 11.0% of CE was resistant to two courses of the combined antibiotic treatments for 14 days (19). However, to the best of the authors’ knowledge, no studies demonstrated the prevalence and management of persistent MDR-CE.”
- It is not clear why the microbiome studies have failed twice - maybe you could describe your findings?
A. We added a supplementary table (quoted in line 128) demonstrating the VS/EF microbiota in these 11 women.
- line 143: I do not understand why these particular taxa has been excluded from the analysis. A fast literature search has revealed that for instance E. coli can be involved in this medical condition. Probably you need to re-analyze the results.
A. We are sorry that the reference quotation was lacking. We added references No.14-17 (line 119 and reference list).
- Were there swabs/cultures taken at the time of infection? Were the species involved identified? These would help to discuss and support the use of lincomycin.
A. As has been described in the first-submitted version, swabs/cultures were taken at the time of inflammation (Figure 1). Unfortunately, the bacterial species unique to persistent MDR-CE were not found in this small sample size (line 126-128).
- The authors briefly mentioned that some women were taking prebiotics/probiotics. This would massively influence treatment outcomes so it should be described in detail.
A. We added information on prebiotics/probiotics that some women were taking (freeze-dry Lactobacillus products and/or lactoferrin supplements, lines 213-214).
- Minor suggestion (line 50): the study described here published elsewhere so please add reference
A. We added reference No.5 (line 52).
Round 2
Reviewer 2 Report
In this study, the authors had reported six cases of persistent MDR-CE in infertile women, and found out oral lincomycin administration (14-day, 1,500mg/day) was effective in the eradication of ES-PCs in these women. This manuscript potentially is interesting, however, it requires major revision.
Firstly and most importantly, it’s confusing how the authors had performed the microbiota analysis? Was it only based on 16S rRNA sequencing with ITS, or it’s based on metagenomic analysis. For the former, the results may not be convincing, especially without ITS sequencing.
Secondly, the whole text requires further elaboration. I suggest the authors draft a table, and put in the relevance between the changes in microbiota with different treatment of antibiotics. Also with the changes in the patients’ condition. This will make a lot of sense cause it clearly showed the effect of the administration of antibiotics.
Thirdly, there’re a large number of writing errors, and we will get into those after the authors have made substantial revision. I also suggest the authors consider seeking an expert from English speaking counties to go over the whole text.
Author Response
Thank you so much for your review comments.
Your suggestions are quite right.
I would decline the manuscript.
Reviewer 3 Report
I have no further comments.
Author Response
Thank you very much.
