Chinese Clinical Trial Registry to COVID-19, Where is the Way Out to the Diagnosis and Treatment Therapy
YaYun Wu1, HuaYe Jiang1, Xun Huang1*
1Departments of Infection Control, Xiangya Hospital, Central South University, Changsha，HuNan 410008,China
*Corresponding author:Xun Huang，MD, Department of Infection Control, Xiangya Hospital, Central South University, Changsha ， HuNan 410008,China (Email: huangxun@mail.csu.edu.cn)
To the Editor:
During the epidemic period of Coronavirus Disease 2019 (COVID-19), many doctors and researchers conducted clinical trial on COVID-19 in China. Until 04:00 am 16 April , 2020, there were 598 clinical trials on COVID-19 registered in Chinese Clinical Trial Register (ChiCTR), including 309 (51.67%) interventional trials and 248 (41.47%) observational trials and 41 （6.86%） diagnostic trials. There were 43 studies have been withdrawn1.We analyze the data for the period, 6 clinical trials were registered in January (1.23-1.31), all of them were interventional studies.There were 291 clinical trials registered in February (2.1-2.29), including 193 (66.32%) interventional studies， 83 (28.52%) observational studies and 15 (5.16%) diagnostic studies.There were 254 clinical trials registered in March (3.1-3.31), including 93 (36.61%) interventional studies,138 (54.33%) observational studies and 23 (9.06%) diagnostic studies. There were 47 clinical trials registered in Apri...
Chinese Clinical Trial Registry to COVID-19, Where is the Way Out to the Diagnosis and Treatment Therapy
YaYun Wu1, HuaYe Jiang1, Xun Huang1*
1Departments of Infection Control, Xiangya Hospital, Central South University, Changsha，HuNan 410008,China
*Corresponding author:Xun Huang，MD, Department of Infection Control, Xiangya Hospital, Central South University, Changsha ， HuNan 410008,China (Email: huangxun@mail.csu.edu.cn)
To the Editor:
During the epidemic period of Coronavirus Disease 2019 (COVID-19), many doctors and researchers conducted clinical trial on COVID-19 in China. Until 04:00 am 16 April , 2020, there were 598 clinical trials on COVID-19 registered in Chinese Clinical Trial Register (ChiCTR), including 309 (51.67%) interventional trials and 248 (41.47%) observational trials and 41 （6.86%） diagnostic trials. There were 43 studies have been withdrawn1.We analyze the data for the period, 6 clinical trials were registered in January (1.23-1.31), all of them were interventional studies.There were 291 clinical trials registered in February (2.1-2.29), including 193 (66.32%) interventional studies， 83 (28.52%) observational studies and 15 (5.16%) diagnostic studies.There were 254 clinical trials registered in March (3.1-3.31), including 93 (36.61%) interventional studies,138 (54.33%) observational studies and 23 (9.06%) diagnostic studies. There were 47 clinical trials registered in April (4.1-4.16), including 17 (36.17%) interventional studies, 27 (57.45%) observational studies and 3 (6.38%) diagnostic studies. The purpose of these interventional clinical trials is to explore the effects of different therapies on COVID-19, while the purpose of these observational clinical trials is to summarize the epidemiological characteristics,clinical symptoms and prognosis of COVID-19.
From January to February, the number of people infected with the novel coronavirus (SARS-CoV-2) increased rapidly in China and the most important task is to treat the patients, so the researchers pay more attention to interventional clinical trials. COVID-19 was gradually controlled in China after March ,thus more efforts were made to summarize the epidemiological characteristics, clinical manifestations and prognosis of COVID-19 by china experts. Therefore, clinical trials in March and April focused on observational studies mostly.Changes in the types and quantities of clinical trials from January to April also reflect the trend of COVID-19 in China.
There were 95 clinical trials about severe and critical cases, 8 clinical trials about deaths, 12 clinical trials about newborn and children, 5 clinical trials about the elderly among the 598 studies.Relevant literature showed that the newborn can be infected by pregnant women with COVID-192. And there were two clinical trials on mother-to-child transmission of COVID-19.
The minimum duration of these clinical trials was 6 days and the maximum duration was 3 years. Most of them were short-term trials and many studies last 1 to 6 months because it is not easy to find patients with COVID-19 and collect specimens when COVID-19 is controlled.There was no gender requirement for participants.Patients specimens included respiratory tract specimens (sputum, throat swab), saliva, blood, feces, urine, tissue specimens.Among these clinical trials, the minimum number of subjects was 8, which reflected the insufficient sample size of some trials.Clinical trials are usually exclusive, and if a patient participates in one intervention trial, he or she cannot join in another study.With the control of COVID-19 in China, the number of people infected goes down. Therefore, some clinical trials may not be able to recruit enough patients and researchers can not draw reliable conclusions without sufficient sample size.
COVID-19 was confirmed by fluorescent reverse transcription polymerase chain reaction (RT-PCR) detection of positive nucleic acid of SARS-CoV-2, however, this technique is time-consuming and laborious. If there are a large number of suspected patients, the detection speed may be slow when use PCR technique only.The lung CT scan of patients with COVID-19 showed lesions, therefore, artificial intelligence imaging system can also play a role in diagnosis. It can complete the screening of suspected cases in a short time, and assists the imaging diagnosis under high intensity work.And there were two studies about the application of artificial intelligence imaging system in the diagnosis of COVID-19.
According to the Chinese COVID-19 Diagnosis and Treatment Protocol (7th edition) 3, symptomatic support therapy and antiviral therapy are the most important treatment .Among the clinical trials of antiviral drugs, there were 16 studies on chloroquine phosphate, 6 studies on interferon ,11 studies on lopinavir/ritonavir, 1 studies on ribavirin, 4 studies on azvudine and 4 studies on abidor.Among the clinical trials of treatment options in severe and critical cases, there were 4 studies on extracorporeal membrane oxygenation(ECMO) techniques, 11 studies on convalescent patients’ plasma therapy, 2 studies on blood purification therapy, 4 studies on glucocorticoid therapy, 6 studies on monoclonal antibody therapy, and 22 studies on stem cell therapy.People died from COVID-19 were severe and critical patients usually,so we want to find appropriate treatment through the studies of severe and critical cases and reduce the mortality.COVID-19 can not only injure the body of patients but also affect their psychological state. People often feel anxiety and fear during outbreaks of infectious disease, so the study of psychology is important too. There were 37 studies on psychologic status of health care workers and patients. With these psychological studies and guidance, fear and anxiety of patients may be reduced.There were 126 studies about Traditional Chinese Medicine and it also played an important role in the treatment of COVID-19.
At present, the spread of COVID-19 are controlled basically in China, but the situation is getting worse in other countries.The imported transmission between different countries will make the epidemic difficult to control, so it is urgent to develop an effective and safe vaccine.There were 5 clinical trials on COVID-19 vaccine registered in ChiCTR. One of which has completed phase I clinical trial, conducted by Institute of biological engineering, academy of military sciences.108 subjects have been vaccinated, including three groups: low-dose group, medium-dose group and high-dose group (36 subjects each group).And the researchers started phase Ⅱ clinical trial already, this is the first COVID-19 vaccine project which has started phase Ⅱ clinical trial in the world.In addition to China, the process of vaccine research is also under way in other countries and it is hopeful to develop an effective vaccine in the near future.
Although COVID-19 has been basically controlled in China, these clinical trials can provide experience for future recurrence and provide reference for the diagnosis and treatment in other countries.The concept of Community of Shared Future for Mankind (CSFM) tell us that only if COVID-19 is under control in all countries can we get out of current predicament. It is hopeful that the results of these clinical trials will play a role in the control of COVID-19 and bring us normal life as soon as possible.
References
1.Index of clinical trials on COVID-19（Updated to 04:00 AM Beijing time, 16 April , 2020)
(http://www.chictr.org.cn/uploads/documents/2020/04/16/88f0c7bb71dc44efb5...)
2.Chen H, Guo J, Wang C, et al. Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records[J]. Lancet,2020,395(10226):809-815.
3.Notice on the issuance about diagnosis and treatment protocol of COVID-19 (7th edition):General office of the national health commission [2020] No.184(http://www.gov.cn/zhengce/zhengceku/2020-03/04/content_5486705.htm)
We thank Dr Jones and Professor Franklin’s insightful and constructive response to our systematic review of the incidence and prevalence of intravenous medication errors in the UK. We appreciate and are grateful for their consideration and the opportunity to respond to their observation.
They are absolutely right to suggest that this is an example of both the limitations of our systematic review methodology, and the importance of grey literature accessing wider datasets as part of these reviews. Our protocol allowed us to contact authors of papers for more detailed data, however did not provide for occasions where authors were not contactable, and did not include grey literature. Two independent data extractors flagged that the data in the original publication [1] was ambiguous. When it was clear that further data was not accessible through direct contact with the author a consensus decision was taken to present only the data that we could reliably associate with IV medication errors from the paper and acknowledge this limitation.
As the correspondents rightly suggest, by supplanting the thesis data into the analysis, we identify 1773 intravenous doses, and 789 errors, resulting in a weighted prevalence estimate of 451/1000 administrations (95% CI 420–482), however the limitations related to the definition and operationalisation of errors, and how they affect estimates still hold, particularly around the impact of including “wrong time” errors into the...
We thank Dr Jones and Professor Franklin’s insightful and constructive response to our systematic review of the incidence and prevalence of intravenous medication errors in the UK. We appreciate and are grateful for their consideration and the opportunity to respond to their observation.
They are absolutely right to suggest that this is an example of both the limitations of our systematic review methodology, and the importance of grey literature accessing wider datasets as part of these reviews. Our protocol allowed us to contact authors of papers for more detailed data, however did not provide for occasions where authors were not contactable, and did not include grey literature. Two independent data extractors flagged that the data in the original publication [1] was ambiguous. When it was clear that further data was not accessible through direct contact with the author a consensus decision was taken to present only the data that we could reliably associate with IV medication errors from the paper and acknowledge this limitation.
As the correspondents rightly suggest, by supplanting the thesis data into the analysis, we identify 1773 intravenous doses, and 789 errors, resulting in a weighted prevalence estimate of 451/1000 administrations (95% CI 420–482), however the limitations related to the definition and operationalisation of errors, and how they affect estimates still hold, particularly around the impact of including “wrong time” errors into these syntheses.[2,3]
This experience has guided us well in subsequent reviews. In a systematic review on the prevalence and nature of drug-related problems in hospitalised children and young people in England [4] the protocol explicitly permitted the use of grey literature and thesis data in line with Cochrane recommendations.[5] Thus we identified the summarised nature of Ghaleb’s data in the published article and extracted granular data direct from the thesis.
We join Jones and Franklin in reminding future reviewers to be mindful of the data that exists in grey literature such as theses and government reports, and to ensure that strategies are incorporated into protocols and search strategies to accommodate these important data sources.
REFERENCES
1 Ghaleb MA, Barber N, Franklin BD, et al. The incidence and nature of prescribing and medication administration errors in paediatric inpatients. Arch Dis Child 2010;95:113–8. doi:10.1136/adc.2009.158485
2 McLeod MC, Barber N, Franklin BD. Methodological variations and their effects on reported medication administration error rates. BMJ Qual Saf 2013;22:278–89. doi:10.1136/bmjqs-2012-001330
3 Keers RN, Williams SD, Cooke J, et al. Causes of Medication Administration Errors in Hospitals: a Systematic Review of Quantitative and Qualitative Evidence. Drug Saf 2013;36:1045–67. doi:10.1007/s40264-013-0090-2
4 Sutherland A, Phipps DL, Tomlin S, et al. Mapping the prevalence and nature of drug related problems among hospitalised children in the United Kingdom: a systematic review. BMC Pediatr 2019;19:486. doi:10.1186/s12887-019-1875-y
5 Lefebvre C, Glanville J, Briscoe S, et al. Chapter 4: Searching for and selecting studies. In: Higgins J, Thomas J, Chandler J, et al., eds. Cochrane Handbook for Systematic Reviews of Interventions. Cochrane 2021. http://www.training.cochrane.org/handbook
We read this article with great interest. Given differences among countries in preparation and administration practices for intravenous medicines, it is an important contribution to the literature.
Sutherland et al. state that their calculation of the incidence of intravenous medication errors may be an underestimate (1), as they were not able to clearly differentiate intravenous from non-intravenous administrations in the study by Ghaleb et al. (2) We are writing to highlight refined data related to the Ghaleb et al. study, which will be useful to readers interested in interpreting the review’s findings.
Specifically, Table 2 of the review reports that in the Ghaleb et al. study, 85 infusions (5.5%) of a total of 1,554 contained at least one error. However, the Ghaleb et al. study reports data relating to all routes of administration, and not just the intravenous route (2). The total of 1,554 observed doses therefore includes both intravenous and other routes of administration, with the number of intravenous doses not reported in the published paper. Consequently, the incidence of intravenous medication errors reported Table 2 for the Ghaleb et al. study is artificially low. This is likely to considerably influence the systematic review’s pooled estimate of the incidence of intravenous medication errors, (1) as Ghaleb et al. (2) contributes 60% of the observations included in this calculation.
The PhD thesis on which the paper by Ghaleb et al. is bas...
We read this article with great interest. Given differences among countries in preparation and administration practices for intravenous medicines, it is an important contribution to the literature.
Sutherland et al. state that their calculation of the incidence of intravenous medication errors may be an underestimate (1), as they were not able to clearly differentiate intravenous from non-intravenous administrations in the study by Ghaleb et al. (2) We are writing to highlight refined data related to the Ghaleb et al. study, which will be useful to readers interested in interpreting the review’s findings.
Specifically, Table 2 of the review reports that in the Ghaleb et al. study, 85 infusions (5.5%) of a total of 1,554 contained at least one error. However, the Ghaleb et al. study reports data relating to all routes of administration, and not just the intravenous route (2). The total of 1,554 observed doses therefore includes both intravenous and other routes of administration, with the number of intravenous doses not reported in the published paper. Consequently, the incidence of intravenous medication errors reported Table 2 for the Ghaleb et al. study is artificially low. This is likely to considerably influence the systematic review’s pooled estimate of the incidence of intravenous medication errors, (1) as Ghaleb et al. (2) contributes 60% of the observations included in this calculation.
The PhD thesis on which the paper by Ghaleb et al. is based contains more information. (3) It states that 751 intravenous doses were observed, which therefore represents a more appropriate denominator than 1,554 to use in calculating the incidence of intravenous medication errors.
As noted in the footnote to Table 2 of the systematic review (1), it was only possible to extract information on ‘intravenous administration rate’ errors from the Ghaleb et al. paper, (2) giving a total of 85 such errors. However, more detail is available from the thesis, which states that 190 intravenous errors were observed in total. (3) This number might therefore be a more appropriate numerator for the incidence of intravenous medication errors in the Ghaleb et al. study, although the thesis does not state if the 190 intravenous errors occurred in 190 intravenous doses, or if more than one error was observed during some administrations.
These refined data result in a maximum intravenous error incidence of 25% for the Ghaleb et al. study (190 errors in 751 intravenous doses). Use of these refined data is therefore likely to result in a considerably higher pooled estimate of the incidence of intravenous medication errors than that originally calculated in the systematic review. (1)
This case serves to highlight some of the potential limitations of systematic review methodology and the importance of drawing on supplementary data and grey literature in selected situations when specific details are not available in the peer-reviewed article.
REFERENCES
1. Sutherland A, Canobbio M, Clarke J, et al. Incidence and prevalence of intravenous medication errors in the UK: a systematic review. Eur J Hosp Pharm 2018;27:3-8. http://dx.doi.org/10.1136/ejhpharm-2018-001624
2. Ghaleb MA, Barber N, Franklin BD, et al. The incidence and nature of prescribing and medication administration errors in paediatric inpatients. Arch Dis Child 2010;95(2):113-8. http://dx.doi.org/10.1136/adc.2009.158485
3. Ghaleb MAA. The incidence and nature of prescribing and administration errors in paediatric inpatients [PhD]. University of London, 2006.
I) We agree with Dr. Van den Eynde that since tedizolid is a more potent inhibitor than linezolid, it is administered at lower doses. Thus, the MAO inhibition would be lower. This is probably the reason why there have been no reports regarding serotoninergic toxicity. However, the possibility of MAO inhibition cannot be ruled out, especially when tedizolid is administered together with serotoninergic drugs. We would like to emphasize that the spontaneous reporting of suspected adverse reactions is useful to identify potential signals that suggest a causal association between a medicinal product and a previously unknown reaction. Whether this suspected adverse reaction is a signal, it should be confirmed by further reports.
II) In our article we do not affirm that it is a serotonin syndrome or a serotonin toxicity, since, in fact, we do not have enough clinical information to confirm it. We only discuss the possibility that the hypertensive crisis could be related to the co-administration of tedizolid and other serotoninergic drugs. Our position is well defined in the following paragraph of the article: “The causality of hypertension as an adverse drug reaction due to the co-administration of tedizolid and other serotonergic treatments was evaluated using the algorithm of Naranjo et al, obtaining a final score of 3. According to this value, the relationship between tedizolid and the hypertensive crisis should be classified as possible, as we were not able to rule ou...
I) We agree with Dr. Van den Eynde that since tedizolid is a more potent inhibitor than linezolid, it is administered at lower doses. Thus, the MAO inhibition would be lower. This is probably the reason why there have been no reports regarding serotoninergic toxicity. However, the possibility of MAO inhibition cannot be ruled out, especially when tedizolid is administered together with serotoninergic drugs. We would like to emphasize that the spontaneous reporting of suspected adverse reactions is useful to identify potential signals that suggest a causal association between a medicinal product and a previously unknown reaction. Whether this suspected adverse reaction is a signal, it should be confirmed by further reports.
II) In our article we do not affirm that it is a serotonin syndrome or a serotonin toxicity, since, in fact, we do not have enough clinical information to confirm it. We only discuss the possibility that the hypertensive crisis could be related to the co-administration of tedizolid and other serotoninergic drugs. Our position is well defined in the following paragraph of the article: “The causality of hypertension as an adverse drug reaction due to the co-administration of tedizolid and other serotonergic treatments was evaluated using the algorithm of Naranjo et al, obtaining a final score of 3. According to this value, the relationship between tedizolid and the hypertensive crisis should be classified as possible, as we were not able to rule out the involvement of other factors.”
References
1. Flanagan S, Bartizal K, Minassian SL, et al. In vitro, in vivo, and clinical studies of tedizolid to assess the potential for peripheral or central monoamine oxidase interactions. Antimicrob Agents Chemother 2013;57:3060–6.
2. Moore N, Berdaï D, Blin P, Droz C. Pharmacovigilance - The next chapter. Therapie. 2019 Dec;74(6):557-567.
3. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239–45.
4. de Castro Julve M, Miralles Albors P, Ortonobes Roig S, et al. Hypertensive crisis following the administration of tedizolid: possible serotonin syndrome. Eur J Hosp Pharm 2018;0:1-3.
We note, upon critical appraisal of this case report, two shortcomings:
(I) the authors provide a one-sided and inaccurate extrapolation to clinical practice from the literature data on tedizolid;
(II) the authors do not adhere to well-established ‘diagnostic decision rules for serotonin toxicity’: the Hunter criteria.<1>
I. In gauging the MAO-inhibiting potential of both antibiotics, de Castro Julve et al. rightly note that ‘tedizolid appears to be a more potent inhibitor in vitro of MAO-A than linezolid’ <2>– but neglect to mention (a) that tedizolid is also four to sixteen (or – depending on the source – ‘two to eight’)<3> times more potent than linezolid at treating most gram-positive infections;<4> and (b) that tedizolid is therefore administered at a lower dose than is linezolid (200mg/day vs. 600mg/12 hours).<3> This likely leads, in practice, to less tedizolid-induced (vs. linezolid-induced) MAO-inhibition<3>, as evidenced by the clinically insignificant potentiation of the tyramine pressor response (TYR30)<2>, and to less potential for serotonergic drug interactions<5>, as further evidenced by the fact that no changes in the murine head twitch response occur, even at plasma tedizolid concentrations which exceed – ‘by up to ~25-fold’ – the Cmax observed in humans at the clinical dose of 200mg/day.<3>
II. The detection in their patient of a hypertensive crisis ‘suspected to be an adverse r...
We note, upon critical appraisal of this case report, two shortcomings:
(I) the authors provide a one-sided and inaccurate extrapolation to clinical practice from the literature data on tedizolid;
(II) the authors do not adhere to well-established ‘diagnostic decision rules for serotonin toxicity’: the Hunter criteria.<1>
I. In gauging the MAO-inhibiting potential of both antibiotics, de Castro Julve et al. rightly note that ‘tedizolid appears to be a more potent inhibitor in vitro of MAO-A than linezolid’ <2>– but neglect to mention (a) that tedizolid is also four to sixteen (or – depending on the source – ‘two to eight’)<3> times more potent than linezolid at treating most gram-positive infections;<4> and (b) that tedizolid is therefore administered at a lower dose than is linezolid (200mg/day vs. 600mg/12 hours).<3> This likely leads, in practice, to less tedizolid-induced (vs. linezolid-induced) MAO-inhibition<3>, as evidenced by the clinically insignificant potentiation of the tyramine pressor response (TYR30)<2>, and to less potential for serotonergic drug interactions<5>, as further evidenced by the fact that no changes in the murine head twitch response occur, even at plasma tedizolid concentrations which exceed – ‘by up to ~25-fold’ – the Cmax observed in humans at the clinical dose of 200mg/day.<3>
II. The detection in their patient of a hypertensive crisis ‘suspected to be an adverse reaction to tedizolid’<2> on the fourth day of treatment, is not a valid diagnostic criterion for even a tentative assessment of ‘serotonin syndrome’ – note, furthermore, that this nomenclature is increasingly considered outmoded: serotonin surplus occurs on a toxicity spectrum<1>, and is preferably consistently referred to as ‘serotonin toxicity’. The absence of observed spontaneous/inducible/ocular clonus or hyperreflexia in the patient, precludes – by all recognized criteria – a diagnosis of possible serotonin toxicity.<1>
Van den Eynde Vincent (first author) has nothing to disclose.
Gillman Peter Kenneth (second/corresponding author: ken.psychotropical@gmail.com) has nothing to disclose.
---
Bibliography (<endnotes>):
1 Dunkley ECJ, Isbister GK, Sibbritt D, et al. The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity. Q J Med 2003;96:635-42.
2 de Castro Julve M, Miralles Albors P, Ortonobes Roig S, et al. Hypertensive crisis following the administration of tedizolid: possible serotonin syndrome. Eur J Hosp Pharm 2018;0:1-3.
3 Rybak JM, Roberts K. Tedizolid Phosphate: a Next-Generation Oxazolidinone. Infect Dis Ther 2015;4:1-14.
4 Flanagan S, Bartizal K, Minassian SL, et al. In Vitro, In Vivo, and Clinical Studies of Tedizolid To Assess the Potential for Peripheral or Central Monoamine Oxidase Interactions. Antimicrob Agents Chemother 2013;57:3060-6.
5 Burdette SD, Trotman R. Tedizolid: The First Once-Daily Oxazolidinone Class Antibiotic. Clin Infect Dis 2015;61:1315-21.
Chinese Clinical Trial Registry to COVID-19, Where is the Way Out to the Diagnosis and Treatment Therapy
Show MoreYaYun Wu1, HuaYe Jiang1, Xun Huang1*
1Departments of Infection Control, Xiangya Hospital, Central South University, Changsha，HuNan 410008,China
*Corresponding author:Xun Huang，MD, Department of Infection Control, Xiangya Hospital, Central South University, Changsha ， HuNan 410008,China (Email: huangxun@mail.csu.edu.cn)
To the Editor:
During the epidemic period of Coronavirus Disease 2019 (COVID-19), many doctors and researchers conducted clinical trial on COVID-19 in China. Until 04:00 am 16 April , 2020, there were 598 clinical trials on COVID-19 registered in Chinese Clinical Trial Register (ChiCTR), including 309 (51.67%) interventional trials and 248 (41.47%) observational trials and 41 （6.86%） diagnostic trials. There were 43 studies have been withdrawn1.We analyze the data for the period, 6 clinical trials were registered in January (1.23-1.31), all of them were interventional studies.There were 291 clinical trials registered in February (2.1-2.29), including 193 (66.32%) interventional studies， 83 (28.52%) observational studies and 15 (5.16%) diagnostic studies.There were 254 clinical trials registered in March (3.1-3.31), including 93 (36.61%) interventional studies,138 (54.33%) observational studies and 23 (9.06%) diagnostic studies. There were 47 clinical trials registered in Apri...
We thank Dr Jones and Professor Franklin’s insightful and constructive response to our systematic review of the incidence and prevalence of intravenous medication errors in the UK. We appreciate and are grateful for their consideration and the opportunity to respond to their observation.
They are absolutely right to suggest that this is an example of both the limitations of our systematic review methodology, and the importance of grey literature accessing wider datasets as part of these reviews. Our protocol allowed us to contact authors of papers for more detailed data, however did not provide for occasions where authors were not contactable, and did not include grey literature. Two independent data extractors flagged that the data in the original publication [1] was ambiguous. When it was clear that further data was not accessible through direct contact with the author a consensus decision was taken to present only the data that we could reliably associate with IV medication errors from the paper and acknowledge this limitation.
As the correspondents rightly suggest, by supplanting the thesis data into the analysis, we identify 1773 intravenous doses, and 789 errors, resulting in a weighted prevalence estimate of 451/1000 administrations (95% CI 420–482), however the limitations related to the definition and operationalisation of errors, and how they affect estimates still hold, particularly around the impact of including “wrong time” errors into the...
Show MoreWe read this article with great interest. Given differences among countries in preparation and administration practices for intravenous medicines, it is an important contribution to the literature.
Sutherland et al. state that their calculation of the incidence of intravenous medication errors may be an underestimate (1), as they were not able to clearly differentiate intravenous from non-intravenous administrations in the study by Ghaleb et al. (2) We are writing to highlight refined data related to the Ghaleb et al. study, which will be useful to readers interested in interpreting the review’s findings.
Specifically, Table 2 of the review reports that in the Ghaleb et al. study, 85 infusions (5.5%) of a total of 1,554 contained at least one error. However, the Ghaleb et al. study reports data relating to all routes of administration, and not just the intravenous route (2). The total of 1,554 observed doses therefore includes both intravenous and other routes of administration, with the number of intravenous doses not reported in the published paper. Consequently, the incidence of intravenous medication errors reported Table 2 for the Ghaleb et al. study is artificially low. This is likely to considerably influence the systematic review’s pooled estimate of the incidence of intravenous medication errors, (1) as Ghaleb et al. (2) contributes 60% of the observations included in this calculation.
The PhD thesis on which the paper by Ghaleb et al. is bas...
Show MoreI) We agree with Dr. Van den Eynde that since tedizolid is a more potent inhibitor than linezolid, it is administered at lower doses. Thus, the MAO inhibition would be lower. This is probably the reason why there have been no reports regarding serotoninergic toxicity. However, the possibility of MAO inhibition cannot be ruled out, especially when tedizolid is administered together with serotoninergic drugs. We would like to emphasize that the spontaneous reporting of suspected adverse reactions is useful to identify potential signals that suggest a causal association between a medicinal product and a previously unknown reaction. Whether this suspected adverse reaction is a signal, it should be confirmed by further reports.
II) In our article we do not affirm that it is a serotonin syndrome or a serotonin toxicity, since, in fact, we do not have enough clinical information to confirm it. We only discuss the possibility that the hypertensive crisis could be related to the co-administration of tedizolid and other serotoninergic drugs. Our position is well defined in the following paragraph of the article: “The causality of hypertension as an adverse drug reaction due to the co-administration of tedizolid and other serotonergic treatments was evaluated using the algorithm of Naranjo et al, obtaining a final score of 3. According to this value, the relationship between tedizolid and the hypertensive crisis should be classified as possible, as we were not able to rule ou...
Show MoreWe note, upon critical appraisal of this case report, two shortcomings:
Show More(I) the authors provide a one-sided and inaccurate extrapolation to clinical practice from the literature data on tedizolid;
(II) the authors do not adhere to well-established ‘diagnostic decision rules for serotonin toxicity’: the Hunter criteria.<1>
I. In gauging the MAO-inhibiting potential of both antibiotics, de Castro Julve et al. rightly note that ‘tedizolid appears to be a more potent inhibitor in vitro of MAO-A than linezolid’ <2>– but neglect to mention (a) that tedizolid is also four to sixteen (or – depending on the source – ‘two to eight’)<3> times more potent than linezolid at treating most gram-positive infections;<4> and (b) that tedizolid is therefore administered at a lower dose than is linezolid (200mg/day vs. 600mg/12 hours).<3> This likely leads, in practice, to less tedizolid-induced (vs. linezolid-induced) MAO-inhibition<3>, as evidenced by the clinically insignificant potentiation of the tyramine pressor response (TYR30)<2>, and to less potential for serotonergic drug interactions<5>, as further evidenced by the fact that no changes in the murine head twitch response occur, even at plasma tedizolid concentrations which exceed – ‘by up to ~25-fold’ – the Cmax observed in humans at the clinical dose of 200mg/day.<3>
II. The detection in their patient of a hypertensive crisis ‘suspected to be an adverse r...