A systematic review of the impacts of oral tetracycline class antibiotics on antimicrobial - PowerPoint Presentation

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A systematic review of the impacts of oral tetracycline class antibiotics on antimicrobial resistance in normal human flora

Robinson TRUONG1,2, Vincent TANG1, Troy GRENNAN3 & Darrell H.S. TAN1, 2, 4, 51. Faculty of Medicine, University of Toronto, 2. Centre for Urban Health Solutions, St. Michael’s Hospital, 3. Division of Infectious Diseases and Department of Medicine, University of British Columbia, 4. Division of Infectious Diseases, St. Michael’s Hospital, 5. Department of Medicine, St. Michael’s Hospital

SP77 & Abstract #168

Robinson Truong (he/him)

MSc Candidate in Medical Science at University of TorontoSt. Michael’s Hospital – MAP Centre of Urban Health SolutionsHBSc in Biomedical Science at Ryerson UniversityUndergraduate thesis in cilia biologyAsian Community AIDS Services (ACAS)

Problems with Syphilis and AMR

Canada’s rate of new syphilis infections has dramatically increased by 167% from 2008 to 2017This surge of syphilis transmission poses a growing threat to public health, especially among gay, bisexual and other men who have sex with men (gbMSM).Antimicrobial resistance (AMR) presents a roadblock to treating increasingly resistant strains of organisms including Neisseria gonorrhoea, and Treponema pallidum, as well as other community-acquired pathogens.Background

Investigating Tetracyclines and AMR

Doxycycline is a tetracycline class antibiotic that has been widely used to treat community-acquired infectionsThere is an emerging interest in daily oral doxycycline for use as pre-exposure prophylaxis (PrEP) against sexually transmitted infections (STI).To understand how much the use of these antibiotics as PrEP may add to the existing threat of antimicrobial resistance (AMR), we conducted a systematic review (CRD#42017077320) of the impacts of chronic oral tetracycline class antibiotics on the development of AMR in normal flora.Background

Primary

To assess the effect of long-term oral exposure to tetracycline class antibiotics on the acquisition of tetracycline class AMR in normal host flora among adults.Objectives

To evaluate the development of

cross-resistance

to non-tetracycline antibiotics with tetracycline therapy.

To evaluate the

bacterial STI incidence

with tetracycline therapy.

Secondary

Eligibility Criteria

Randomized controlled trialsStudy outcomes:emergence of antimicrobial resistance geneschanges in minimum inhibitory concentration (MIC)changes in tetracycline class antibiotic susceptibilityNo combination antibiotic therapy for the intervention.Methods

We searched MEDLINE, EMBASE and Cochrane

Library with terms

for RCTs assessing oral tetracyclines, but not AMR outcomes to maximize sensitivity.

Two reviewers (RT, VT) independently screened the articles

Assessed risk of bias for all relevant articles based on the CONSORT checklist

It was not possible to conduct meta-analyses due to heterogeneity in the way outcomes were reported

We summarized findings descriptively, grouping results according to the types of AMR outcomes reported

Search

Strategy and Study Selection

Analysis

Figure 1 PRISMA Flowchart

ResultsaReasons for exclusion are mutually exclusive.

7 articles address 1

o

objective on tetracycline AMR

3 articles address 2

o

objective on cross-resistance

No

a

rticles address 2

o

objective on bacterial STI

Table 1 Assessment of Risk of Bias of Included Studies

ResultsStudy

Assessment of Risk of Bias

Randomization

Concealment of Treatment Allocation

Blinding of Outcome Assessment

Attrition

Quality of Statistical Analysis

Overall

Sack, 1978

High

Moderate

Low

Low

Low

Moderate

Arthur, 1990

Low

Unclear

Unclear

Low

Low

Moderate

Feres, 1999

Unclear

Unclear

Unclear

Low

Low

High

Feres, 2002

Unclear

Unclear

Unclear

Low

Low

High

Rodrigues, 2004

Unclear

Unclear

Unclear

Low

Low

High

Ozolins, 2004

Low

Moderate

LowModerateLowModerateBrill, 2015LowUnclearHighLowLowModerate

Table 2 Summary of Studies

ResultsStudy CharacteristicsDetails of StudiesCountry of studiesUnited States (n=5), United Kingdom (n=3), Kenya (n=1), and Thailand (n=1).

Sample size20-253

Age18-83 years old

Duration of treatment

2-18 weeks

Interventions and

Dose

Doxycycline (n=5,

100-200mg/daily)

Tetracycline (n=1, 500mg/daily)

Oxytetracycline (n=1, 500mg/daily)

and

Minocycline (500mg/daily)

Comparators

Placebo (n=1)

Non-antibiotic controls (n=3)

Nothing (n=1)

Combination of placebo and alternative antibiotics (n=1)

Combination of placebo and non-antibiotic

controls (n=1)

Timing of final

AMR assessment since the start of treatment

3 days to 12 months

AMR outcome methods

Inoculation of samples onto plates containing tetracyclines (n=4)

Disk diffusion (n=2)

Etest (n=1).

Studies in Subgingival Flora

Study

Study Characteristics

Results

Population

N

Intervention(s)

Comparator(s)

Follow-up

AMR Method

Outcome(s)

b

Intervention

Comparator

Difference

Effect

c

Feres

, 1999 and

Feres

, 2002

d

Adults with periodontitis, US

20

SRP + doxycycline 200mg

qd

po

on day 1, then 100mg

qd

po

for the next 13 days

SRP

3, 7, 14, 17, 21, 28 and 90 days

Inoculation onto plates containing 4 µg/mL doxycycline

%isolates resistant to doxycycline in plaque

Increase at 3, 7, 14, 17 and 21 days

Minimal change over 90 days

p<0.05

↑

No increase at 28 and 90 days

Minimal change over 90 days

NOD

↔?

Increase over 90 days (p<0.01)

Minimal change over 90 days

OD↑?%isolates resistant to doxycycline in saliva Increase at 3, 7, 14, 17, 21, and 28 daysMinimal change over 90 daysp<0.05↑No increase at 90 daysMinimal change over 90 daysNOD

↔?

Increase over 90 days

(p<0.01)

Minimal change over 90 days

OD

↑?

%subgingival sites with doxycycline-resistant

S. sanguis isolates in plaqueIncrease at 14 and 17 daysMinimal change over 90 daysp<0.05↑No increase at 3, 7, 21, 28 and 90 daysMinimal change over 90 daysNOD↔?Rodrigues, 2004Adults with periodontitis, US20 SRP + tetracycline 500mg bid po for 2 weeksSRP1 week, 3, 6 and 12 months post-treatmentInoculation onto plates containing 4 µg/mL doxycycline%isolates resistant to tetracycline in plaqueIncrease at 1 week and 6 monthsMinimal change over 12 monthsp<0.05↑No increase at 3 and 12 monthsMinimal change over 12 monthsNOD↔?%sites with resistant P. gingivalis in plaqueDecrease over 12 months (p<0.05)Minimal change over 12 monthsOD↓?%sites with resistant T. forsythia in plaqueMinimal change over 12 monthsMinimal change over 12 monthsNOD↔?%sites with resistant A. actinomycetemcomitans in plaqueMinimal change over 12 monthsMinimal change over 12 monthsNOD↔?

Results addressing tetracycline AMR

Table 3 Impact of Tetracyclines on Burden of Resistant Isolates and Antibiotic Susceptibilitya

a

bid

= twice per day, CI = confidence interval, NOD = No observable difference, NR = exact values not reported, OD = observable difference,

po

= oral, qd = once per day, SPR = Scaling Root Planing.bUnless otherwise specified, values are mean ± SD, or median (interquartile range).cArrows indicates the direction of effect on burden of resistant isolates or antibiotic susceptibility.dStudies by Feres et al., 2002 and Feres et al., 1999 have the same study sample.

Studies in Gastrointestinal Flora

Study

Study Characteristics

Results

Population

N

Intervention(s)

Comparator(s)

Follow-up

AMR Method

Outcome(s)

b

Intervention

Comparator

Difference

Effect

c

Sack, 1978

Peace corps volunteers, Kenya

39

Doxycycline 100mg bid

po

on day 1, then

qd

po

for 3 weeks

Nothing

3 and 5 weeks

Disk diffusion method with 30 µg tetracycline

%commensal

E. coli

and pathogenic

E. coli

isolates resistant to tetracycline in stool

Increase at 3 weeks (21



100)

Increase at 3 weeks (6.1



25)

OD

↑?

Decrease at 5 weeks (100



39)

Decrease at 5 weeks (2523)NOD↔?Arthur, 1990United States soldiers, Thailand253Doxycycline 100mg po for 5 weeks + placebo mefloquine weeklyOral mefloquine 250mg weekly for 5 weeks + placebo doxycycline daily5 weeksDisk diffusion method with 30 µg tetracycline%individuals with tetracycline resistant commensal E. coli isolates in stoolIncrease at 5 weeks (7699)Increase at 5 weeks (6986)Difference at 5 weeks (p=0.01)↑Results addressing tetracycline AMR

Studies in Skin Flora

Study

Study Characteristics

Results

Population

N

Intervention(s)

Comparator(s)

Follow-up

AMR Method

Outcome(s)

b

Intervention

Comparator

Difference

Effect

c

Ozolins

, 2004

Patients with acne vulgaris, UK

391

Oxytetracycline 500mg bid

po

for 18 weeks

Placebo

qd

po

and 5% benzoyl peroxide topical cream twice daily

18 weeks

Inoculation onto plates containing 5 µg/mL tetracycline

Change in mean growth score for prevalence of tetracycline resistant Propionibacteria in skin swab

No change over 18 weeks

(0.0 (p=1))

Minimal change over 18 weeks (-0.3 (p=0.003))

No difference (NR)

↔

Minocycline 100mg

qd

po

for 18 weeks

No change over 18 weeks

(0.0 (p=1))

Minimal change over 18 weeks (-0.3 (p=0.003))

No difference (NR)

↔

Results addressing tetracycline AMRStudies in Upper Respiratory FloraStudyStudy CharacteristicsResultsPopulationNIntervention(s)

Comparator(s)

Follow-up

AMR Method

Outcome(s)

b

Intervention

Comparator

DifferenceEffectcBrill, 2015Patients with chronic bronchitis and COPD, UK49Doxycycline 100mg qd po for 13 weeksPlacebo qd po for 13 weeks13 weeksEtestFactor change in MIC100 in sputumNRNR3.74, p=0.01, 95% CI: 1.46-9.58↑

Table 4 Impact of Oral Tetracyclines on Cross-Resistance

Results addressing cross-resistance

Study

Study Characteristics

Results

Population

N

Intervention(s)

Comparator(s)

Follow-up

Outcome(s)

Non-tetracycline antibiotics

Intervention

Comparator

Difference

Effect

b

Studies in gastrointestinal flora

Sack, 1978

Peace corps volunteers, Kenya

39

Doxycycline 100mg bid

po

on day 1, then

qd

po

for 3 weeks

Nothing

3 and 5 weeks

%isolates of non-ETEC and ETEC in stool with resistance to multiple

antibiotics

Streptomycin

Sulfonamide

Ampicillin

NR

NR

OD at 3 weeks, but NOD at 5 weeks

↑?

↔?

Arthur, 1990

United States soldiers, Thailand

253

Doxycycline 100mg

po

for 5 weeks + placebo

mefloquine weeklyOral mefloquine 250mg weekly for 5 weeks + placebo doxycycline daily5 weeksProportion of individuals with non-ETEC strains resistant to ≥2 antibiotics in stoolAmpicillinChloramphenicol ErythromycinGentamicinKanamycinNeomycinStreptomycinTrimethoprim/SulfamethoxazoleIncrease at 5 weeks(79%93%)

Increase at 5 weeks (65%86%)

NOD

↔?

Studies in skin flora

Ozolins

, 2004

Patients with acne vulgaris, UK

391Oxytetracycline 500mg bid po for 18 weeksPlacebo qd po and 5% benzoyl peroxide topical cream twice daily18 weeks Change in mean growth score for prevalence of resistant Propionibacteria in skin swabErythromycinClindamycinNo increase over 18 weeks(-0.1, p=0.362)(-0.0, p=1.000)No increase over 18 weeks(–0.5, p<0.001)NOD ↔?Minocycline 100mg qd po for 18 weeksNo increase over 18 weeks(-0.2, p=0.122)(-0.2, p=0.085)No increase over 18 weeks(–0.5, p<0.001)NOD ↔?

The effects of oral tetracyclines on AMR seem to be somewhat transient in subgingival, gastrointestinal and upper respiratory flora

The effects of oral tetracyclines on cross-resistance to non-tetracyclines seem to be minimalCurrent studies on the efficacy of doxycycline as syphilis PrEP and post-exposure prophylaxis (PEP).Bolan, 2015 for PrEP and Molina, 2018 for PEP.Fusca, 2020. High acceptability of doxycycline as syphilis PrEP and PEP among gbMSM Canadians.Doxycycline syphilis PrEP vs PEPStrengths: RCT, maximized sensitivity, methods to assess AMR are all validated and acceptableLimitations: Moderate to high risk of bias, heterogeneity of outcomes and analysis, and no studies on emergence of resistance genesConclusion

Thanks to those who supported this project!

Acknowledgement

A systematic review of the impacts of oral tetracycline class antibiotics on antimicrobial resistance in normal human flora

Thank you for listening If you have any questions, feel free to email me at Robinson.truong@mail.utoronto.ca