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. 2018 Aug 3;2018(8):CD008069. doi: 10.1002/14651858.CD008069.pub2

Antibiotics and antivirals for dementia and mild cognitive impairment

Yan Zhou 1, Ming Yang 1, Bi Rong Dong 1, Tao Chen 2, Akshay Nair 3,✉
PMCID: PMC6513043

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

The objective of this review is to evaluate the efficacy and adverse effects of antibiotics (except D‐cycloserine) and antiviral agents for dementia and mild cognitive impairment.

Background

Dementia and mild cognitive impairment are common mental health problems affecting those over 65, especially of those over 80. It is estimated that 24.3 million people have dementia today, with 4.6 million new cases of dementia every year Ferri 2005). According to the Global Burden of Disease estimates for the 2003 World Health Report, dementia contributed 11.2% of years lived with disability in people aged 60 years and older; more than stroke (9.5%), musculoskeletal disorders (8.9%), cardiovascular disease (5.0%), and all forms of cancer (2.4%)( WHO 2003). The number of people affected will double every 20 years to 81.1 million by 2040 (Ferri 2005). Alzheimer's disease (AD) is the main cause of dementia, accounting for 50 to 70% of the cases, followed by vascular dementia (30 to 40%) and mixed dementia (15 to 20%) (Cacabelos 2008).

The term mild cognitive impairment (MCI) describes a degree of impairment short of that meeting criteria for dementia. It is associated with increased risk of progression to dementia, decreased quality of life and increased disability (Tabert 2002, Plassman 2008, Giovanni 2008). The prevalence of MCI varies from 7.7% to 22% (Plassman 2008, Giovanni 2008).

The aetiology of Alzheimer's disease is not well understood but includes genetic predisposition and environmental conditions (Giacobini 2007).

HIV and syphilis are the only known infectious cause of slowly progressive dementia. The evidence concerning the treatment of HIV dementia is sufficient to warrant a review in its own right. Whilst it is recognised that the remaining putative infectious causes of dementia have little or nothing in common with each other, we believe that the interest in this area warrants a review of what little evidence there is.

Whilst it is well established that syphilis is associated with dementia, the evidence to support a role for other infectious agents in dementia is conflicting. The next section briefly summarises this evidence.

Description of the condition

There is sparse and sometimes contradictory evidence concerning the possibility that infectious agents can cause dementia. Spirochetes (Noguchi 1913, Miklossy 2004), C. pneumoniae (Balin 1998, Mahony 2000, Ossewaarde 2000, Little 2004, Hideki 2005) and virus such as Herpes Simplex Virus 1 (HSV1) (Lin 1997, Leissring 1998, Itzhaki 1997) and HIV were found might cause dementia. Dementia induced by HIV will not be discussed in this review.

1. Spirochetes

Treponema pallidum is the pathogenic agent of syphilis. It is generally accepted that Treponema pallidum is responsible for dementia (Noguchi 1913), (Miklossy 2008a). The clinical and pathological hallmarks of the atrophic form of general paresis caused by Treponema pallidum are similar to those occurring in AD. Treponema pallidum can cause cortical atrophy, microgliosis and amyloid deposition.

Borrelia burgdorferi, which was first identified in 1982, is the pathogenic microorganism of Lyme disease. Miklossy J (Miklossy 1993) first reported the possible relationship between AD and Borrelia burgdorferi in 1993, and he reported similar results in the following years (Miklossy 2004, Miklossy 2006). However, other authors got controversial results (Gutacker 1998, Marques 2000, Galbussera 2008). Borrelia burgdorferi or the poorly degradable debris are powerful inflammatory cytokine inducers, they may damage the brain and induce amyloid plaques (Miklossy 2008).

2. Chlamydia pneumoniae

In addition to its role in pneumonia, there is evidence associating C. pneumoniae with lung infection, atherosclerosis (Kern 2009) and Alzheimer's disease (Balin 1998). It was Balin and his coworkers (Balin 1998) who first identified C. pneumoniae in the brains of AD patients by using polymerase chain reaction (PCR). But the following studies (Nochlin 1999, Gieffers 2000) got conflicting results. C. pneumoniae may damage the brain directly by increasing the number of amyloid plaques (Little 2004), influencing the levels of tau protein and Ab42 (Paradowski 2007) and impair the brain indirectly by promoting transmigration of monocytes across blood‐brain barrier (McIntyre 2003), altering junctional complex proteins of human brain vascular endothelia (McIntyre 2002) or causing persisting infection (Itzhaki 2004).

3. Herpes Simplex Virus Type One

Herpes Simplex Virus Type 1 infections are tiny, clear, fluid‐filled blisters that most often occur on the face. The link between HSV‐1 and Alzheimer's disease was first found in 1980 (Middleton 1980). HSV1 DNA has been found in brain of a high proportion of elderly people (Itzhaki 2006), but neither HSV1 proteins nor intact virions have been detected in AD brain tissue (Lellouch 2000), the relationship between HSV1 and AD is still unclear (Robinson 2004). HSV‐1 glycoprotein B is similar with beta‐amyloid protein carboxyl putative neurotoxic, nucleation and assembly domains, and it may be associated with AD involves the induction of the neurotropic cytokine, interleukin 6 (Pyles 2001). Vaccine against HSV1 was studied to prevent AD (Lin 2001), but there are still many problems need to be answered before it can be used in human beings.

Description of the intervention

Based on the findings above, antibiotics for those bacterium or virus may play a role in the treatment of dementia. We will review the efficacy of antibiotics (except D‐cycloserine) and antiviral agents for dementia.

1.penicillin

Penicillin is commonly used to treat infection induced by Spirochetes and is potentially useful for dementia.

2.tetracyclines and rifampin

Some researchers had found that tetracyclines, rifampin and D‐cycloserine might have a therapeutic role in patients with mild to moderate Alzheimer's disease (Loeb 2004, Jones 2002 ).

3.Acyclovir

Herpes simplex encephalitis can be treated with acyclovir, and the acyclovir may be effective. It should be noted that acyclovir cannot eliminate pathogens but stop them from replicating.

How the intervention might work

a) Mechanisms of the antibacterial agents might be

  1. Eliminating microorganisms. For example, penicillin can treat syphilis by getting rid of pathogens.

  2. Suppressing inflammation. Some antibiotics, such as macrolides, can suppress inflammation. The possible mechanisms might include: an inhibitory effect on hypersecretion of cytokine; an inhibitory effect on the accumulation of neutrophils; effects on lymphocytes and other cells (Giamarellos‐Bourboulis 2008).

  3. Novel actions of antimicrobials. Studies in vitro have shown that tetracyclines and rifampin could influence the accumulation of amyloid beta peptide and the subsequent development of beta‐amyloid fibrils (Tomiyama 1996, Forloni 2001).

  4. Action of antimicrobials at neurotransmitter sites. Other mechanisms such as influencing special receptors such as NMDA receptor that associated with memory (Chessell 1991).

Why it is important to do this review

Recent studies have indicated that microorganisms may be related to the onset of dementia, and antibiotics such as doxycycline and rifampin might have a therapeutic role in patients with mild to moderate Alzheimer's disease (Loeb 2004). It may represent an attractive therapeutic target for the treatment of dementia and mild cognitive impairment. There is a need for a Cochrane systematic review to assess the evidence.

Objectives

The objective of this review is to evaluate the efficacy and adverse effects of antibiotics (except D‐cycloserine) and antiviral agents for dementia and mild cognitive impairment.

Methods

Criteria for considering studies for this review

Types of studies

Only randomized controlled trials will be included.

Types of participants

Reviewed trials will include patients with mild cognitive impairment as well as any kind and severity of dementia including Alzheimer's disease. The diagnostic criteria should be globally accepted, such as the Diagnostic and Statistical Manual of Mental Disorders (APA 1994), the criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (Dubois 2007), the International Classification of Diseases version 10 (WHO 1993) or equivalent criteria.

Types of interventions

  1. Antibiotic(s) vs. placebo.

  2. Antibiotic(s) plus other therapy (or therapies) vs. other therapy (or therapies).

Types of outcome measures

Primary outcomes

  1. Improvement of cognition (as measured by psychometric tests)

  2. Mortality

  3. Improvement of behaviour disturbance

  4. Activities of daily living

  5. Time from mild cognitive impairment to dementia

  6. Clinical global impression of change

  7. Adverse effects (such as the drop‐out rate and overall rate of adverse effects)

  8. Global severity of dementia

  9. Institutionalization

Secondary outcomes

  1. Caregiver burden

  2. Mood

Search methods for identification of studies

Electronic searches

We searched ALOIS (www.medicine.ox.ac.uk/alois) ‐ the Cochrane Dementia and Cognitive Improvement Group’s Specialised Register on 11 August 2011. The search terms used were: antibiotic OR Doxycycline OR Vibramycin OR Monodoxin OR Rifampin OR Liviatin OR Hydramycin OR Rifampicin OR Fluoroquinolone OR 2 Liviatin OR Hydramycin OR Rifampicin OR Fluoroquinolone OR minocycline OR antiviral OR anti‐viral.

ALOIS is maintained by the Trials Search Co‐ordinator of the Cochrane Dementia and Cognitive Improvement Group and contains studies in the areas of dementia prevention, dementia treatment and cognitive enhancement in healthy and in those with mild cognitive impairment. The studies are identified from:  

  1. Monthly searches of a number of major healthcare databases: Medline, Embase, Cinahl, Psycinfo and Lilacs

  2. Monthly searches of a number of trial registers: ISRCTN; UMIN (Japan's Trial Register); the WHO portal (which covers ClinicalTrials.gov; ISRCTN; the Chinese Clinical Trials Register; the German Clinical Trials Register; the Iranian Registry of Clinical Trials and the Netherlands National Trials Register, plus others)

  3. Quarterly search of The Cochrane Library’s Central Register of Controlled Trials (CENTRAL)

  4. Six‐monthly searches of a number of grey literature sources: ISI Web of Knowledge Conference Proceedings; Index to Theses; Australasian Digital Theses

To view a list of all sources searched for ALOIS see About ALOIS on the ALOIS website.

Details of the search strategies used for the retrieval of reports of trials from the healthcare databases, CENTRAL and conference proceedings can be viewed in the ‘methods used in reviews’ section within the editorial information about the Dementia and Cognitive Improvement Group.

Additional searches were performed in many of the sources listed above to cover the timeframe from the last searches performed for ALOIS to ensure that the search for the review was as up‐to‐date and as comprehensive as possible. The search strategies used can be seen in Appendix 1.

The search of August 2011 retrieved a total of 1425 results. After a first‐assess and a de‐duplication of these results the authors were left with 133 records to further assess for potential inclusion or exclusion within the review.

Searching other resources

Authors will need to do this: We will search identified citations for additional trials. We will contact the first author of identified trials for additional references and unpublished data.

Authors will need to do this: Manufacturing companies will be approached for additional trials (both published and unpublished). We will check the website of the Food and Drug Administration (FDA 2009) for more information.

Data collection and analysis

Selection of studies

From the title, abstract or descriptors, two reviewers (Zhou and Yang) will review the literature searches to identify potentially relevant trials for full review. Searches of bibliographies and texts will be conducted to identify additional studies. Both reviewers will independently read the abstract and methods sections of the papers to select the trials for inclusion in this review. Differences between reviewers will be measured by consensus, or if necessary referred to the third author (Birong Dong).

Data extraction and management

Zhou and Chen will extract data for the trials independently. Principal investigators of included studies will be contacted, when required, to provide additional data or confirmation of methodological aspects of the study in order to enhance the results of this review.

Data in table or graphic form will be used if published and authors will be requested to confirm data extraction and provide clarification and additional information for the review. Studies to be included will be subjected to quality assessment by both reviewers.

Data will be input to RevMan 5.0.

Assessment of risk of bias in included studies

Two reviewers (Zhou and Yang) will then rank studies for quality by looking at randomization, blinding, patient selection, placebo, reporting of results and statistical analysis according to the Cochrane approach for judging risk of bias outlined by Higgins 2008.

Measures of treatment effect

For continuous variables such as the change from baseline, the mean change, the standard error of the mean change and the number of patients for each treatment group of individual studies will be extracted or calculated. In this case a zero correlation between the measurements at baseline and assessment time will be assumed.

For trials that have used the same rating scale to assess outcome, the mean difference (historically termed weighted mean difference) will be calculated, with 95% Confidence Intervals (CI). Where different rating scales or tests have been used, the measure of the treatment difference is the standardized mean difference. For crossover trials, cluster‐randomized trials and outcome data that are time‐to‐event, the inverse‐variance method will be used.

For binary outcomes, such as clinical improvement or no clinical improvement, individual and pooled statistics will be calculated as relative ratios (RR) or odds ratio (OR) with 95% CIs, determined by the character of data.

Unit of analysis issues

For numeric value from scales, the unit should be scores. The time unit will be transformed into the same according to the primary studies.

Dealing with missing data

Information will be requested from the trial authors when sufficient details are not available in published reports.

For binary outcomes, the missing data will be approached using the intention‐to‐treat analysis. If intention‐to‐treat data are not available in the publications, we shall seek 'on‐treatment' data (i.e. the data of those who complete the trial) and indicate it as such.

Assessment of heterogeneity

For pooled effects I2 will be calculated. Significant heterogeneity is defined as when I2 > 40% (Higgins 2008). Where there is evidence of heterogeneity of the treatment effect between trials, then either only homogenous results will be pooled, or a random‐effects model will be used.

Assessment of reporting biases

Funnel plots will be performed to test for publication bias.

Data synthesis

Data will be combined using RevMan 5.0.

Subgroup analysis and investigation of heterogeneity

Subgroup analysis of the efficacy of antibiotics for different kinds of dementia or mild cognitive impairment will be performed, if adequate studies are found. With enough information, we will analyse the impact of antibiotics on general health (e.g. COPD/UTI) as a possible mediating variable. We will perform subgroup analyses based on different kind of antibiotics for dementia or mild cognitive impairment if there are enough studies.

Sensitivity analysis

Sensitivity analysis will be conducted, where possible, to explore the influence of including certain trials or not, as well as the effects of analysing by intention to treat, on the effect size. We will conduct a subgroup analysis if there are sufficient data.

Acknowledgements

We wish to acknowledge the consumer reviewer Mingming Zhang for comments on the protocol.

Appendices

Appendix 1. Search: August 2011

Source
  		Search strategy Hits retrieved
1. ALOIS (www.medicine.ox.ac.uk/alois) Keyword search:
#1 antibiotic OR Doxycycline OR Vibramycin OR Monodoxin OR Rifampin OR Liviatin OR Hydramycin OR Rifampicin OR Fluoroquinolone
#2 Liviatin OR Hydramycin OR Rifampicin OR Fluoroquinolone OR minocycline OR antiviral OR anti‐viral
#3  #1 OR #2		 4
2. MEDLINE In‐process and other non‐indexed citations and MEDLINE 1950‐present (Ovid SP) 1. dement*.ti,ab.
2. exp Dementia/
3. Delirium, Dementia, Amnestic, Cognitive Disorders/
4. alzheimer*.ti,ab.
5. ((cognit* or memory* or mental*) adj3 (declin* or impair* or los* or deteriorat*)).ti,ab.
6. (MCI or aMCI or nMCI).ti,ab.
7. (forgefullness or "memory complain*").ti,ab.
8. (ACMI or ARCD or CIND or AAMI or AACD or MNCD or NCD or mMCI).ti,ab.
9. or/1‐8
10. Antibiotic*.ti,ab.
11. Anti‐Bacterial Agents/
12. Doxycycl*.ti,ab.
13. Vibramycin.ti,ab.
14. Monodoxin.ti,ab.
15. Rifampin*.ti,ab.
16. Liviatin*.ti,ab.
17. Hydramycin*.ti,ab.
18. Rifampicin*.ti,ab.
19. Fluoroquinolone*.ti,ab.
20. Minocycl*.ti,ab.
21. Antivir*.ti,ab.
22. Anti‐vir*.ti,ab.
23. or/10‐22
24. 9 and 23
25. randomized controlled trial.pt.
26. controlled clinical trial.pt.
27. randomi?ed.ab.
28. placebo.ab.
29. drug therapy.fs.
30. randomly.ab.
31. trial.ab.
32. groups.ab.
33. or/25‐32
34. (animals not (humans and animals)).sh.
35. 33 not 34
36. 24 and 35
 		 315
3. EMBASE
1980‐2011 week 31 (Ovid SP)		 1. dement*.ti,ab.
2. exp dementia/
3. alzheimer*.ti,ab.
4. ((cognit* or memory* or mental*) adj3 (declin* or impair* or los* or deteriorat*)).ti,ab.
5. (MCI or aMCI or nMCI).ti,ab.
6. (forgefullness or "memory complain*").ti,ab.
7. (ACMI or ARCD or CIND or AAMI or AACD or MNCD or NCD or mMCI).ti,ab.
8. or/1‐7
9. Antibiotic*.ti,ab.
10. antibiotic agent/
11. Doxycycl*.ti,ab.
12. Vibramycin.ti,ab.
13. Monodoxin.ti,ab.
14. Rifampin*.ti,ab.
15. Liviatin*.ti,ab.
16. Hydramycin*.ti,ab.
17. Rifampicin*.ti,ab.
18. Fluoroquinolone*.ti,ab.
19. Minocycl*.ti,ab.
20. Antivir*.ti,ab.
21. Anti‐vir*.ti,ab.
22. or/9‐21
23. 8 and 22
24. randomi?ed.ab.
25. randomly.ab.
26. RCT.ti,ab.
27. random*.ti.
28. randomized controlled trial/
29. controlled clinical trial/
30. "double‐blind*".ti,ab.
31. "single‐blind*".ti,ab.
32. placebo.ab.
33. groups.ab.
34. or/24‐33
35. 23 and 34
 		 172
4. PSYCINFO
1806‐August week 2 2011 (Ovid SP)		 1. dement*.ti,ab.
2. alzheimer*.ti,ab.
3. exp Dementia/
4. ((cognit* or memory* or mental*) adj3 (declin* or impair* or los* or deteriorat*)).ti,ab.
5. (MCI or aMCI or nMCI).ti,ab.
6. (forgefullness or "memory complain*").ti,ab.
7. (ACMI or ARCD or CIND or AAMI or AACD or MNCD or NCD or mMCI).ti,ab.
8. or/1‐7
9. Antibiotic*.ti,ab.
10. exp Antibiotics/
11. Doxycycl*.ti,ab.
12. Vibramycin.ti,ab.
13. Monodoxin.ti,ab.
14. Rifampin*.ti,ab.
15. Liviatin*.ti,ab.
16. Hydramycin*.ti,ab.
17. Rifampicin*.ti,ab.
18. Fluoroquinolone*.ti,ab.
19. Minocycl*.ti,ab.
20. Antivir*.ti,ab.
21. Anti‐vir*.ti,ab.
22. or/9‐21
23. 8 and 22
24. exp Clinical Trials/
25. trial.ti,ab.
26. placebo.ab.
27. RCT.ti,ab.
28. random*.ti.
29. randomi?ed.ab.
30. randomly.ab.
31. groups.ab.
32. "double‐blind*".ti,ab.
33. "single‐blind*".ti,ab.
34. or/24‐33
35. 23 and 34
 		 41
5. CINAHL (EBSCOhost) S1 TX dement*
S2 (MH "Dementia+") OR (MH "Delirium, Dementia, Amnestic, Cognitive Disorders") 
S3 TX alzheimer*
S4 TX MCI OR aMCI OR nMCI OR mMCI 
S5 TX forgefullness OR "memory complain*" 
S6 TX ACMI OR ARCD OR CIND OR AAMI OR AACD OR MNCD OR NCD OR mMCI 
S7 TX "cognit* impair*" 
S8 S1 or S2 or S3 or S4 or S5 or S6 or S7 
S9 TX Antibiotic*
S10 (MH "Antibiotics") 
S11 TX Doxycycline*
S12 TX Vibramycin*
S13 TX Monodoxin*
S14 TX Rifampin*
S15 TX Liviatin*
S16 TX Hydramycin*
S17 TX Rifampicin* 
S18 TX Fluoroquinolone*
S19 TX Minocycline* 
S20 TX Antivir* 
S21 TX Anti‐vir*
S22 S9 or S10 or S11 or S12 or S13 or S14 or S15 or S16 or S17 or S18 or S19 or S20 or S21 
S23 S8 and S22 
S24 TX random*
S25 TX RCT OR CCT 
S26 TX trial 
S27 (MH "Clinical Trials") OR (MH "Randomized Controlled Trials")
S28 TX placebo 
S29 TX groups 
S30 TX "double‐blind*" OR "single‐blind*" 
S31 S24 or S25 or S26 or S27 or S28 or S29 or S30 
S32 S23 and S31 		 99
6. ISI Web of Knowledge – all databases [includes: Web of Science (1945‐present); BIOSIS Previews (1926‐present); MEDLINE (1950‐present); Journal Citation Reports] Topic=(dementia OR "cognit* impair*" OR MCI OR alzheimer*) AND Topic=(antibiotic OR Doxycycline OR Vibramycin OR Monodoxin OR Rifampin OR Liviatin* OR Hydramycin* OR Rifampicin* OR Fluoroquinolone OR Liviatin* OR Hydramycin* OR Rifampicin* OR Fluoroquinolone OR minocycline OR antiviral OR "anti‐viral") AND Topic=(randomly OR placebo OR groups OR trial OR RCT OR randomized OR randomised)
Timespan=All Years.
Search language=English   Lemmatization=On  
 		 313
7. LILACS (BIREME) #1 demenc$ OR dementia OR alzheimer OR alzheimers OR BPSD [Words] and antibiotic OR Doxycycline OR Vibramycin OR Monodoxin OR Rifampin OR Liviatin OR Hydramycin OR Rifampicin OR Fluoroquinolone [Words]
#2 demenc$ OR dementia OR alzheimer OR alzheimers OR BPSD [Words] and Liviatin OR Hydramycin OR Rifampicin OR Fluoroquinolone OR minocycline OR antiviral OR anti‐viral [Words]
#3 #1 OR #2		 9
8. CENTRAL (The Cochrane Library) (Issue 4 of 4, Oct 2010) #1 "cognit* impair*"
#2 MeSH descriptor Cognition Disorders explode all trees
#3 MCI
#4 ACMI
#5 ARCD
#6 SMC
#7 CIND
#8 BSF
#9 AAMI
#10 LCD
#11 QD OR "questionable dementia"
#12 AACD
#13 MNCD
#14 MCD
#15 "N‐MCI" or "A‐MCI" or "M‐MCI"
#16 (cognit* or memory or cerebr* or mental*) NEAR/3 (declin* or impair* or los* or deteriorat* or degenerat* or complain* or disturb* or disorder*)
#17 "preclinical AD"
#18 "pre‐clinical AD"
#19 "preclinical alzheimer*" or "pre‐clinical alzheimer*"
#20 aMCI OR MCIa
#21 "CDR 0.5" OR "clinical dementia rating scale 0.5"
#22 "GDS 3" OR "stage 3 GDS"
#23 "global deterioration scale" AND "stage 3"
#24 "Benign senescent forgetfulness"
#25 "mild neurocognit* disorder*"
#26 (prodrom* NEAR/2 dement*)
#27 episodic* NEAR/2 memory
#28 "preclinical dementia" OR "pre‐clinical dementia"
#29 episodic NEAR/2 memory
#30 "pre‐clinical dementia" OR "preclinical dementia"
#31 (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26 OR #27 OR #28 OR #29 OR #30)
#32 dement* OR alzheimer* OR AD OR lewy
#33 MeSH descriptor Dementia explode all trees
#34 (#31 OR #32 OR #33)
#35 MeSH descriptor Anti‐Bacterial Agents explode all trees
#36 antibiotic*
#37 Doxycycline OR Vibramycin OR Monodoxin OR Rifampin OR Liviatin OR Hydramycin OR Rifampicin OR Fluoroquinolone
#38 Liviatin OR Hydramycin OR Rifampicin OR Fluoroquinolone OR minocycline OR antiviral OR anti‐viral
#39 (#36 OR #37 OR #38)
#40 (#35 OR #39)
#41 (#40 AND #34)
#42 (#41)
#43 "accession number" near pubmed
#44 "accession number" near2 embase
#45 (#43 OR #44)
#46 (#41 AND NOT #45)		 329
9. Clinicaltrials.gov (www.clinicaltrials.gov) dementia OR cognition OR MCI OR alzheimers OR AD | antibiotic OR Doxycycline OR Vibramycin OR Monodoxin OR Rifampin OR Liviatin OR Hydramycin OR Rifampicin OR Fluoroquinolone OR Liviatin OR Hydramycin OR Rifampicin OR Fluoroquinolone OR minocycline OR antiviral OR anti‐viral 60
10. ICTRP Search Portal (http://apps.who.int/trialsearch) [includes: Australian New Zealand Clinical Trials Registry; ClinicalTrilas.gov; ISRCTN; Chinese Clinical Trial Registry; Clinical Trials Registry – India; Clinical Research Information Service – Republic of Korea; German Clinical Trials Register; Iranian Registry of Clinical Trials; Japan Primary Registries Network; Pan African Clinical Trial Registry; Sri Lanka Clinical Trials Registry; The Netherlands National Trial Register] dementia OR cognition OR MCI OR alzheimers OR AD | antibiotic OR Doxycycline OR Vibramycin OR Monodoxin OR Rifampin OR Liviatin OR Hydramycin OR Rifampicin OR Fluoroquinolone OR Liviatin OR Hydramycin OR Rifampicin OR Fluoroquinolone OR minocycline OR antiviral OR anti‐viral 83
TOTAL before de‐duplication 1425
TOTAL after de‐dupe and first‐assess 133
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What's new

Date Event Description
3 August 2018 Amended This protocol, published in 2009, was withdrawn from the Cochrane Library in August 2018 due to lack of progress.
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Contributions of authors

All correspondence: Yan Zhou and Birong Dong

Drafting of Review versions: Yan Zhou and Ming Yang

Search for trials: CDCIG

Obtaining copies of trial reports: Yan Zhou and Ming Yang

Selection of trials for inclusion/exclusion: Yan Zhou, Ming Yang and Birong Dong

Extraction of data: Yan Zhou and Tao Chen

Entry of data: Yan Zhou and Ming Yang

Interpretation of data analyses: Yan Zhou and Tao Chen

Consumer: Mingming Zhang

Sources of support

Internal sources

  • None, Other.

External sources

  • No sources of support supplied

Declarations of interest

None known.

Notes

This protocol, published in 2009, was withdrawn from the Cochrane Library in August 2018 due to lack of progress.

Withdrawn from publication for reasons stated in the review

References

Additional references

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