Treatment failure of bacterial vaginosis is not associated with higher loads of Atopobium vaginae and Gardnerella vaginalis

Ferreira, C.; Donders, Gilbert; Pàrada, Cristina Maria Garcia de Lima; Tristão, Andréa da Rocha; Fernandes, Thaiz; Silva, Márcia Guimarães da; Marconi, Camila

doi:10.1099/jmm.0.000561

Cited by 14 publications

(10 citation statements)

References 46 publications

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“…Recent studies evaluating pre-treatment vaginal microbiota composition on MNZ efficacy have reported inconsistent results, likely due to differences in patient exclusion criteria, time point of treatment outcome assessment, drug regimen, and methods to collect and quantify the vaginal microbiota. One study that employed a similar drug regimen (oral MNZ) and sample collection methods to the clinical cohorts evaluated here supported our results, finding higher pre-treatment loads of antibiotic-target species, Gv and A. vaginae, associated with BV treatment efficacy 19 . Other studies that used different sample collection methods and antibiotic regimens did not explicitly evaluate the pre-treatment ratio of BV-associated bacteria to Lactobacillus spp.…”

Section: Discussionsupporting

confidence: 85%

“…Recurrence is associated with several host factors including previous episodes of BV, douching, and sexual activity, but no one factor emerges as a single driver of treatment failure 11,[15][16][17][18] . In addition, associations between vaginal microbiota composition and BV recurrence have been reported but remain poorly understood, with several studies citing conflicting results 15,17,19 .…”

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confidence: 99%

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Quantitative modeling predicts mechanistic links between pre-treatment microbiome composition and metronidazole efficacy in bacterial vaginosis

et al. 2020

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Bacterial vaginosis is a condition associated with adverse reproductive outcomes and characterized by a shift from a Lactobacillus-dominant vaginal microbiota to a polymicrobial microbiota, consistently colonized by strains of Gardnerella vaginalis. Metronidazole is the first-line treatment; however, treatment failure and recurrence rates remain high. To understand complex interactions between Gardnerella vaginalis and Lactobacillus involved in efficacy, here we develop an ordinary differential equation model that predicts bacterial growth as a function of metronidazole uptake, sensitivity, and metabolism. The model shows that a critical factor in efficacy is Lactobacillus sequestration of metronidazole, and efficacy decreases when the relative abundance of Lactobacillus is higher pre-treatment. We validate results in Gardnerella and Lactobacillus co-cultures, and in two clinical cohorts, finding women with recurrence have significantly higher pre-treatment levels of Lactobacillus relative to bacterial vaginosis–associated bacteria. Overall results provide mechanistic insight into how personalized differences in microbial communities influence vaginal antibiotic efficacy.

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Section: Discussionsupporting

confidence: 85%

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confidence: 99%

Quantitative modeling predicts mechanistic links between pre-treatment microbiome composition and metronidazole efficacy in bacterial vaginosis

et al. 2020

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“…It is unclear if it is caused by resistance of the BV pathogens to metronidazole and which mechanisms are acting in vivo . A recent study has demonstrated that failure of treatment of BV with metronidazole is not associated with higher loads of G. vaginalis and Atopobium vaginae ( 21 ). Isolates from G. vaginalis subgroups A and D are intrinsically resistant against metronidazole, but the underlying mechanism is unknown ( 14 ).…”

Section: Introductionmentioning

confidence: 99%

Metatranscriptome Analysis of the Vaginal Microbiota Reveals Potential Mechanisms for Protection against Metronidazole in Bacterial Vaginosis

Deng

Gottschick

Bhuju

et al. 2018

mSphere

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Bacterial vaginosis is a serious issue for women in their reproductive years. Although it can usually be cured by antibiotics, the recurrence rate is very high, and some women do not respond to antibiotic therapy. The reasons for that are not known. Therefore, we undertook a study to detect the activity of the complete microbiota in the vaginal fluid of women who responded to antibiotic therapy and compared it to the activity of the microbiota in women who did not respond. We found that one of the most important pathogens in bacterial vaginosis, Gardnerella vaginalis, has activated genes that can repair the DNA damage caused by the antibiotic in those women that do not respond to therapy. Suppressing these genes might be a possibility to improve the antibiotic therapy of bacterial vaginosis.

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“…The potential for non-antibiotic-target bacterial populations to act as a sink for MNZ and alter efficacy is similar to a concept that has been previously explored in bacterial ecology and termed the "the inoculum effect (IE)", which describes an increase in antibiotic MICs due to increased initial bacterial load and decreased per cell antibiotic concentration. 55 This model result implies that MNZ efficacy may be dependent on highly variable pre-treatment relative abundances of 19 Other studies that used different sample collection methods and antibiotic regimens did not explicitly evaluate the pretreatment ratio of BV-associated bacteria to Lactobacillus spp. ; generally suggested there was an association between total Lactobacillus relative abundance and successful treatment.…”

Section: Discussionmentioning

confidence: 99%

Novel systems analysis elucidates the influence of personalized variation in microbiome composition on metronidazole efficacy in bacterial vaginosis

Lee

Cheu

Lemke

et al. 2020

Preprint

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Bacterial vaginosis (BV) is a syndrome of the female reproductive tract associated with adverse reproductive outcomes and characterized by a shift from a Lactobacillus (LB)-dominant vaginal microbiota to a polymicrobial, anaerobic microbiota, consistently colonized by strains of Gardnerella vaginalis (Gv). The first-line treatment for BV is metronidazole (MNZ); however, treatment failure and recurrence rates remain high. To gain insight into complex interactions between target species (Gv) and non-target Lactobacillus species (Lactobacillus iners (Li)) with MNZ and understand their respective roles in efficacy, we developed an ordinary differential equation model that predicts bacterial growth as a function of drug uptake, metabolism, proliferation, and MNZ sensitivity. Model findings revealed a critical factor in MNZ efficacy may be Li sequestration of MNZ, and that efficacy decreases when the relative abundance of Li is higher pre-treatment. These results were validated in Gv and Li co-cultures (p < 0.001), and in two clinical cohorts, finding women with recurrent BV had significantly lower pre-treatment levels of BV-associated bacteria relative to Lactobacillus spp. (p = 0.0366; p = 0.0484). Overall, model results support a mechanism where non-target Lactobacillus species sequester MNZ from BV-associated target species, such as Gv, promoting BV recurrence by reducing MNZ bioavailability.

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Treatment failure of bacterial vaginosis is not associated with higher loads of Atopobium vaginae and Gardnerella vaginalis

Abstract: Although G. vaginalis produces several virulence factors and its loads correlate positively with those of A. vaginae, higher cervicovaginal quantities of these bacteria are not associated with treatment failure of BV after oral metronidazole.

Cited by 14 publications

References 46 publications

Quantitative modeling predicts mechanistic links between pre-treatment microbiome composition and metronidazole efficacy in bacterial vaginosis

Quantitative modeling predicts mechanistic links between pre-treatment microbiome composition and metronidazole efficacy in bacterial vaginosis

Metatranscriptome Analysis of the Vaginal Microbiota Reveals Potential Mechanisms for Protection against Metronidazole in Bacterial Vaginosis

Novel systems analysis elucidates the influence of personalized variation in microbiome composition on metronidazole efficacy in bacterial vaginosis

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