- Email: [email protected]
Bacterial vaginosis and surgical site infections
Journal Pre-proof Bacterial Vaginosis and Surgical Site Infections David E. Soper, MD PII:
S0002-9378(19)31107-X
DOI:
https://doi.org/10.1016/j.ajog.2019.09.002
Reference:
YMOB 12873
To appear in:
American Journal of Obstetrics and Gynecology
Received Date: 12 February 2019 Revised Date:
13 August 2019
Accepted Date: 3 September 2019
Please cite this article as: Soper DE, Bacterial Vaginosis and Surgical Site Infections, American Journal of Obstetrics and Gynecology (2019), doi: https://doi.org/10.1016/j.ajog.2019.09.002. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc.
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[Journal for submission: American Journal of Obstetrics & Gynecology, clinical opinion piece] Bacterial Vaginosis and Surgical Site Infections David E. Soper, MD Medical University of South Carolina, Charleston, SC
Address for correspondence:
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David E. Soper, MD
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Division of Obstetrics and Gynecology
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Medical University of South Carolina
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96 Jonathan Lucas Street, Suite 635D
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MSC 619
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Charleston, SC 29425
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Tel: 843-792-5300
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Email: [email protected]
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Word count for text: 2511 (limit for Clinical Opinion, 3000 words)
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Author contributions
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The author was responsible for all content and editorial decisions, and received no honoraria
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related to the development of this manuscript. The author contributed to the research, writing,
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and reviewing of all drafts of this manuscript and approved the final version.
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Funding
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Editorial support in the preparation of this manuscript was provided by Phase Five
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Communications, funded by Symbiomix Therapeutics, LLC, a Lupin Pharmaceuticals company.
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Conflict of Interest Statement
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The author reports no conflict of interest.
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Abstract [197 words; limit: 350 words]
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Bacterial vaginosis (BV) is the most common cause of abnormal vaginal discharge or malodor,
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affecting up to one-third of US women. Most women with BV are unaware of the infection,
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making it difficult to diagnose in the absence of a microscopic examination of vaginal discharge
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or using point-of-care testing. Untreated BV elevates the risk of postoperative surgical
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infections in women undergoing obstetric and gynecologic procedures. Treatment with
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antimicrobial agents that target BV has been shown to reduce the rate of postoperative
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infections following hysterectomy and surgical abortions. Furthermore, in a cost-comparison
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model, screening for and treatment of BV prior to hysterectomy was shown to be superior to
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no screening in terms of infection rates and cost. The BV diagnostic criteria are simple and
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screening tests are inexpensive; BV screening is a relatively fast process in patients who present
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for preoperative appointments. Treatment options approved by the FDA include
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metronidazole, clindamycin, tinidazole, and secnidazole. Given the prevalence of BV and the
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risks associated with operating on a woman with untreated BV, women undergoing
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hysterectomy, surgical abortion, and potentially cesarean delivery should be screened for BV,
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and those who screen positive should be treated with an appropriate antimicrobial agent.
17 18
Keywords: bacterial vaginosis, clindamycin, metronidazole, secnidazole, surgical site infections,
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tinidazole
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1 2
Introduction Bacterial vaginosis (BV) is a common condition among women, with approximately one-
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third of those between 14 and 49 years of age screening positive for BV.1 A similar proportion
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of postmenopausal women also screen positive for BV.2 Among women presenting for care, BV
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is the most prevalent cause of vaginal discharge or malodor; however, most women with BV are
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asymptomatic.1,3 Beyond the discomfort of BV, the condition is associated with several adverse
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outcomes. The link between untreated BV and subsequent sexually transmitted infections (STIs)
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is well established; STIs associated with BV infection include Chlamydia trachomatis, Neisseria
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gonorrhoeae, Trichomonas vaginalis, and herpes simplex virus infection.4-6 Furthermore,
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untreated BV is associated with a substantial increase in the risk of HIV acquisition.7,8 Untreated
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BV also has effects on fertility and pregnancy outcomes, as it has been associated with tubal
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infertility, and an increased risk of preclinical pregnancy loss, spontaneous abortion, and
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preterm delivery.9 Moreover, BV increases the risk of gynecologic and obstetric postoperative
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site infections following cesarean delivery, hysterectomies, and surgical abortions. These
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infections are associated with a range of negative outcomes: longer duration of hospital stay,
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use of emergency department resources, hospital readmission, reoperation, and sepsis.10 The
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aim of this article is to review the literature with regard to the association between BV and
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gynecologic and obstetric postsurgical infections, as well as provide guidance on pre-operative
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BV treatment.
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Etiology of BV
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1
In the National Health and Nutrition Examination Surveys (NHANES), only 16% of
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women who screened positive for BV reported vaginal symptoms, such as vaginal odor,
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wetness, and discharge.3 Given the low proportion of women who report signs of BV and the
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nonspecific nature of the symptoms, dependence on clinical interviews to diagnose BV may
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miss a large proportion of BV cases.11 Therefore, BV is often underdiagnosed and may go
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untreated.12 A variety of modifiable factors are associated with an increased risk of BV,
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including multiple male and female sex partners, a new sex partner, douching, and lack of
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condom use.13
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The precise etiology of BV is unclear, but as we gain understanding of the vaginal
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microbiome, we realize how microbiota play a significant role in the health of the female
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reproductive tract. While diverse microbial communities are considered a healthy sign in most
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sites of the human body (ie, the gastrointestinal system), a healthy female reproductive tract is
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more likely associated with low microbial diversity dominated by one or a few Lactobacillus
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species.14 Species of Lactobacillus have been historically associated with vaginal health in
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reproductive-age women due to the direct and indirect protective nature derived from
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Lactobacillus products, including lactic acid and bacteriocin, which oppose mucus degradation
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and inhibit pathogens. It is generally agreed that BV occurs when Lactobacillus-dominant
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vaginal flora are disrupted, reducing the proportion of lactic acid-producing bacteria and
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increasing the proportion of BV-related bacteria.15,16 In addition, the presence of hydrogen
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peroxide-producing lactobacilli can prevent the growth of pathogens associated with BV.17
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Bacteria that are associated with BV include Gardnerella vaginalis, Megasphaera spp,
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Atopobium vaginae, Dialister spp, Leptotrichia amnionii, Sneathia sanguinegens, 5
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Porphyromonas asaccharolytica, and Prevotella bivia.16,18 In a systematic review of studies that
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incorporated at least one molecular technique (sequencing, PCR, DNA fingerprinting, or DNA
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hybridization), lactobacilli-dominated vaginal micro-environments were associated with vaginal
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health.
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Ethnicity is a major intrinsic factor known to be significantly associated with variance in
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community composition, with Caucasian and Asian women displaying a significantly greater
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prevalence of Lactobacillus spp dominant microbiota compared with Hispanic and black
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women.14,19 These differences may be due to genetic factors that influence mucosal immunity
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or metabolic pathways, which result in preferential conditions for particular species, as well as
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variation in practices such as vaginal douching, which is twice as common in black women
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compared with Caucasians.14,20
12 13 14
Benefits of BV Pretreatment of Surgical Site Infections Surgical site infections that complicate procedures performed by obstetricians and
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gynecologists involve the ascending spread of microorganisms in the vagina and cervix to the
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upper genital tract.21 Surgical sites include the endomyometrium, incised at the time of
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cesarean; the vaginal cuff and paravaginal tissues, incised at the time of hysterectomy; or the
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endometrium, evacuated with uterine curettage in treating disorders of early pregnancies
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(incomplete, missed, or elective abortion). BV microorganisms are commonly isolated from the
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surgical sites of women with a surgical site infection.22,23 Moreover, the concentration of
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potential bacterial pathogens in the vagina of women with BV is increased by 100- to 1000-
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1
fold.24 Studies evaluating perioperative treatment of BV suggest that identifying women with
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BV prior to surgery can lead to a substantial reduction in postoperative infections.25,26
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With regard to pregnancy, BV has been shown to increase the risk of developing
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intrapartum chorioamnionitis, which is an established risk factor for postpartum endometritis.27
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Additionally, BV is associated with postcesarean endometritis with the isolation of BV
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microorganisms in the endometrial cavity of these patients.23 Among women undergoing
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cesarean delivery, the preoperative administration of intravaginal metronidazole gel reduced
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the risk of postcesarean endometritis by 58%.28 In another study, perioperative ampicillin plus
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metronidazole decreased the rate of infections for women undergoing cesarean delivery (38%
10 11
vs 15%) relative to perioperative benzylpenicillin, which does not effectively treat BV.29 In an analysis of 134 patients who underwent abdominal hysterectomy, the rate of
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vaginal-cuff cellulitis or abscess was significantly higher in patients with preoperative BV
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compared with patients without BV (34% vs 11%).22 Similar rates of posthysterectomy infection
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were reported in other studies, with rates of vaginal-cuff and deep infections ranging from 25%
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to 34% – an approximately 3-fold increase in risk relative to populations without BV.10,22,30 The
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association of BV with postoperative infections is further supported by the isolation of BV-
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related organisms such as G. vaginalis from patients with posthysterectomy cuff infections.22
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Treatment of BV prior to hysterectomy was also beneficial. In a randomized trial, preoperative
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treatment with metronidazole resulted in a significantly lower rate of vaginal-cuff infections in
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women with BV who underwent hysterectomy compared with those who did not receive
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treatment for BV (0% vs 36%; P <.05).31 In a larger nationwide study, preoperative treatment
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with antibiotics for BV reduced the rate of severe postoperative infections among women with 7
1
BV by 73%.10 Additionally, compared with placebo, prophylactic intravenous metronidazole in
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women undergoing abdominal hysterectomy reduced the rate of postoperative infections (12%
3
vs 6%) and the duration of hospitalization (9 vs 8 days).32 In the study of perioperative ampicillin
4
plus metronidazole mentioned above, infections related to hysterectomy also decreased (20%
5
vs 3%) relative to perioperative benzylpenicillin.29
6
Screening patients for BV prior to hysterectomy and treating patients who screen
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positive regardless of symptoms is a cost-effective option for preventing vaginal-cuff infections.
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In a study of preoperative screening for BV, the costs of the following presurgical options for
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women undergoing hysterectomy were compared: testing all patients for BV and treating if
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positive, treating all patients for BV, and neither testing nor treating patients for BV.33 Treating
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all patients with metronidazole was associated with the lowest modeled rate of cuff infections
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(4%) and the lowest cost ($593).33 Testing all patients but treating only positive patients was
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similarly cost-effective ($623), with an acceptable rate of cuff infections (4%).33 Although
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treating all patients with metronidazole was modestly more cost-effective in this study,
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treatment following screening would appear to be a more practical option. Single-dose
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metronidazole added to cefazolin as antibiotic prophylaxis does not effectively treat BV; a
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multi-dose regimen of metronidazole is recommended. Moreover, with a prevalence of up to
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30%, the majority of preoperative patients will not require antibiotic therapy for BV prior to
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surgery.3
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Preoperative treatment for BV may also reduce the risk of infection in women post-
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termination of early pregnancy. In one study, the risk of postabortal endometritis was elevated
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6-fold among women with preoperative BV.34 In randomized controlled trials of women with BV 8
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undergoing first-trimester abortions, infection rates were 3- to 4-fold lower among women who
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received preoperative metronidazole or clindamycin.25,26 Perioperative treatment with
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metronidazole has also been reported as an effective option for women with BV undergoing
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abortion, resulting in a risk reduction of approximately one-half for postprocedural upper
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genital tract infections.35 In a recent retrospective study in Sweden with longitudinal follow-up,
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women undergoing voluntary abortion between 2008 and 2015 were screened for chlamydia,
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gonorrhea, mycoplasma, and BV prior to the abortions. Abortion complications,
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bleeding, infection, or incomplete abortion were assessed in women who came to the
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gynecological clinic within 30 days after the procedure. Women who tested positive for one or
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several bacteria when screened and who received antibiotics experienced almost the same rate
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of postabortal infections compared with women who tested negative upon screening.36 While
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approximately 15% of the study participants screened positive for BV, the study was not
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specific for BV.36 In this study, preabortion screening with subsequent antibiotic treatment in
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women who tested positive for certain bacteria appeared to decrease the number of
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postabortion infections. Nevertheless, the data are still not clear as to which bacteria are
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causing the infections. In a recent prospective observational study in Finland, 5279 women
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undergoing hysterectomy for benign indications were given cefuroxime and/or metronidazole.
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Cefuroxime appeared to be effective in prophylaxis against infections while metronidazole
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appeared to be ineffective, with no additional risk-reductive effect when combined with
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cefuroxime.37
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The available evidence suggests a possible benefit of screening and treating patients for
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BV prior to labor, hysterectomy, and surgical abortion. In the American College of Obstetricians 9
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and Gynecologists (ACOG) guidelines for the prevention of infection after gynecologic
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procedures, it was noted that preoperative screening and treatment for BV “can be considered”
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before hysterectomy.38 Given similar evidence linking BV to intrapartum chorioamnionitis and
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postcesarean endometritis,23,27,39 screening for BV at the 35- to 37-week group B streptococcus
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culture visit and treating those with BV should also be considered. In the absence of guidance
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from professional societies, many clinicians may be unaware of the risks of BV during surgical
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interventions and the potential benefits of BV treatment. In the era of “zero tolerance” for
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surgical site infections, preoperative screening for and treatment of BV may allow an additional
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incremental decrease in surgical site infections.
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BV Treatment Options BV can be treated with a variety of oral and intravaginal antibiotic options (Table 1). In
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the 2015 guidelines on sexually transmitted disease management, the CDC recommends BV
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treatment with oral metronidazole 500 mg twice a day for 7 days, intravaginal metronidazole
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gel 5 g once a day for 5 days, or intravaginal clindamycin cream 5 g at bedtime for 7 days.13 The
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alternative regimens recommended by the CDC are oral tinidazole 2 g once daily for 2 days, oral
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tinidazole 1 g once daily for 5 days, oral clindamycin 300 mg twice daily for 7 days, or
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intravaginal clindamycin ovules 100 mg at bedtime for 3 days; however, the CDC noted that
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there are limited data for the efficacy of the alternative options.13 The CDC-recommended
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regimens for BV management have been shown to have roughly equivalent effectiveness within
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trials, but differences in cure definitions and follow-up times limit comparisons across trials.40
10
1
Shorter courses of treatment are often beneficial to ensure patient adherence, and may
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be particularly useful in the setting of preventing surgical site infections. However, shorter
3
courses of treatment may not be as effective as longer ones. For example, the CDC-
4
recommended 2-day option of tinidazole 2 g is not as effective as a 5-day course of tinidazole 1
5
g. In a randomized controlled trial, 5 days of tinidazole 1 g resulted in a significantly better cure
6
rate compared with 2 days of tinidazole 2 g (37% vs 27%; P<0.001).41 Although a single oral
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dose of metronidazole 2 g has been shown to have good efficacy with a 90% cure rate, it is
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important to note that cure was defined as the absence of clue cells and the absence of at least
9
2 other BV-associated symptoms assessed on day 8, which is a short follow-up period relative to
10 11
other studies discussed here. Furthermore, adverse events are more common at this dose.42 Clindamycin 2% and metronidazole gel 1.3% (not to be confused with MetroGel vaginal
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0.75%) are FDA-approved single-dose intravaginal options.43,44 It is important to note that the
13
treatment regimens reviewed have not necessarily been evaluated in the setting of
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preoperative treatment measuring the reduction of surgical site infections.
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A recent addition to the BV therapeutic armamentarium is single-dose treatment with
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oral secnidazole 2 g, which was approved by the FDA for the treatment of BV in 2017.45 In a
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randomized controlled trial, single-dose secnidazole 2 g significantly improved clinical cure
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rates compared with placebo (53% vs 19%; P<0.001).46 Of note, clinical cure in this phase 3 trial
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required that patients meet the following criteria at study days 21 to 30, which are more
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stringent compared with clinical trials performed in earlier years: normal vaginal discharge,
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negative whiff test, and less than 20% of clue cells of total epithelial cell count.46 When
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compared with a 7-day oral metronidazole regimen, a single dose of secnidazole 2 g resulted in 11
1
noninferior clinical cure rates at day 21 (60% vs 60%).47 In an open-label study evaluating
2
safety, common treatment-related adverse events included vulvovaginal candidiasis (5%),
3
nausea (4%), and bad taste (3%).48
4 5 6
Managing BV Prior to Surgery Given the asymptomatic status of the majority of women with BV and the other
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associated difficulties with diagnosing BV,3 screening women for BV prior to obstetric and
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gynecologic surgeries can contribute to further reducing postoperative infections in a safe and
9
cost-effective manner. Evaluating patients with the Amsel criteria is simple, quick, and
10
inexpensive, and can be performed at preoperative appointments. Preoperative BV screening
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should be considered before hysterectomy, surgical abortions, and in the late third trimester of
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pregnancy. To ensure informed decision-making, a discussion about the risks of postoperative
13
infections should be a standard part of patient counseling prior to obstetric and gynecologic
14
surgeries.
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Preoperative management of BV should prioritize effectiveness, adherence, and, in
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some cases, duration of treatment. One of the conventional advantages of single-dose therapy
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is the virtually assured adherence of patients. For preoperative treatment of BV, there is the
18
added advantage of quickly treating BV prior to a scheduled surgery date. Single-dose
19
treatment options (ie, oral secnidazole 2 g, oral metronidazole 2 g, intravaginal metronidazole,
20
or intravaginal clindamycin) should be considered for patients who have preoperative
21
appointments that are less than a week from surgery. If the preoperative appointment is 7 days
22
or more before the date of surgery, clinicians might elect to use one of the multidose regimens 12
1
(see Table 1). For all patients, decisions should be made based on likelihood of adherence,
2
patient preferences for route of administration and dosing, and risk-benefit profiles.
3 4 5
Conclusion Women with BV are at increased risk of adverse pregnancy outcomes and infectious
6
complications following obstetric and gynecologic surgery. The diagnosis of BV is quick,
7
inexpensive, and simple with the use of microscopy or available point-of-care testing. Screening
8
for BV is needed given that it is asymptomatic in most women. Treatment options allow
9
preoperative eradication of BV and may further contribute to lowering the risk of surgical site
10
infections. Future prospective study is needed to clarify the impact of this cost-effective
11
intervention in further reducing the number of women whose procedures will be complicated
12
by surgical site infection.
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1 2 3 4
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41. Livengood CH 3rd, Ferris DG, Wiesenfeld HC, et al. Effectiveness of two tinidazole
2
regimens in treatment of bacterial vaginosis: a randomized controlled trial. Obstet
3
Gynecol 2007;110:302-9.
4
42. Brandt M, Abels C, May T, Lohmann K, Schmidts-Winkler I, Hoyme UB. Intravaginally
5
applied metronidazole is as effective as orally applied in the treatment of bacterial
6
vaginosis, but exhibits significantly less side effects. Eur J Obstet Gynecol Reprod Biol
7
2008;141:158-62.
8 9 10 11 12 13 14
43. Clindesse (clindamycin phosphate) vaginal cream, 2% [prescribing information]. Allegan, MI: Perrigo; 2014. 44. Metronidazole vaginal gel 1.3% [prescribing information]. Bridgewater, NJ: Valeant Pharmaceuticals North America, LLC; 2014. 45. Solosec (secnidazole) oral granules [prescribing information]. Newark, NJ: Symbiomix Therapeutics, LLC; 2017. 46. Schwebke JR, Morgan FG Jr, Koltun W, Nyirjesy P. A phase-3, double-blind, placebo-
15
controlled study of the effectiveness and safety of single oral doses of secnidazole 2 g
16
for the treatment of women with bacterial vaginosis. Am J Obstet Gynecol
17
2017;217:678.e1-9.
18
47. Bohbot JM, Vicaut E, Fagnen D, Brauman M. Treatment of bacterial vaginosis: a
19
multicenter, double-blind, double-dummy, randomised phase III study comparing
20
secnidazole and metronidazole. Infect Dis Obstet Gynecol 2010;2010. pii: 705692.
21 22
48. Chavoustie SE, Gersten JK, Samuel MJ, Schwebke JR. A phase 3, multicenter, prospective, open-label study to evaluate the safety of a single dose of secnidazole 2 g 19
1
for the treatment of women and postmenarchal adolescent girls with bacterial
2
vaginosis. J Womens Health (Larchmt) 2018;27:492-7.
3
20
1
Table 1. Approved treatment regimens for bacterial vaginosis13 Drug formulation
Dose
Frequency and duration
Metronidazole
500 mg
BID for 7 days
Metronidazole
2g
Single dose
Tinidazole
1g
QD for 5 days
Tinidazole
2g
QD for 2 days
Clindamycin
300 mg
BID for 7 days
Secnidazole
2g
Single dose
Metronidazole gel 0.75%
5 g (one full applicator)
QD for 5 days
Metronidazole gel 1.3%
5 g (one full applicator)
Single dose (at bedtime)
Clindamycin cream 2%
5 g (one full applicator)
QD (at bedtime) for 7 days
Clindamycin cream 2% ER
5 g (one full applicator)
Single dose
Clindamycin ovule
100 mg
QD (at bedtime) for 3 days
Oral
Intravaginal
2 3
[Table footnote]
4
BID, twice daily; ER, extended release; QD, once daily.
21
S0002-9378(19)31107-X
DOI:
https://doi.org/10.1016/j.ajog.2019.09.002
Reference:
YMOB 12873
To appear in:
American Journal of Obstetrics and Gynecology
Received Date: 12 February 2019 Revised Date:
13 August 2019
Accepted Date: 3 September 2019
Please cite this article as: Soper DE, Bacterial Vaginosis and Surgical Site Infections, American Journal of Obstetrics and Gynecology (2019), doi: https://doi.org/10.1016/j.ajog.2019.09.002. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc.
1 2 3 4 5 6 7 8 9 10
[Journal for submission: American Journal of Obstetrics & Gynecology, clinical opinion piece] Bacterial Vaginosis and Surgical Site Infections David E. Soper, MD Medical University of South Carolina, Charleston, SC
Address for correspondence:
11
David E. Soper, MD
12
Division of Obstetrics and Gynecology
13
Medical University of South Carolina
14
96 Jonathan Lucas Street, Suite 635D
15
MSC 619
16
Charleston, SC 29425
17
Tel: 843-792-5300
18 19
Email: [email protected]
20 21 22
Word count for text: 2511 (limit for Clinical Opinion, 3000 words)
23
Author contributions
24
The author was responsible for all content and editorial decisions, and received no honoraria
25
related to the development of this manuscript. The author contributed to the research, writing,
26
and reviewing of all drafts of this manuscript and approved the final version.
27 28 1
1 2
Funding
3
Editorial support in the preparation of this manuscript was provided by Phase Five
4
Communications, funded by Symbiomix Therapeutics, LLC, a Lupin Pharmaceuticals company.
5 6
Conflict of Interest Statement
7
The author reports no conflict of interest.
2
1
Abstract [197 words; limit: 350 words]
2
Bacterial vaginosis (BV) is the most common cause of abnormal vaginal discharge or malodor,
3
affecting up to one-third of US women. Most women with BV are unaware of the infection,
4
making it difficult to diagnose in the absence of a microscopic examination of vaginal discharge
5
or using point-of-care testing. Untreated BV elevates the risk of postoperative surgical
6
infections in women undergoing obstetric and gynecologic procedures. Treatment with
7
antimicrobial agents that target BV has been shown to reduce the rate of postoperative
8
infections following hysterectomy and surgical abortions. Furthermore, in a cost-comparison
9
model, screening for and treatment of BV prior to hysterectomy was shown to be superior to
10
no screening in terms of infection rates and cost. The BV diagnostic criteria are simple and
11
screening tests are inexpensive; BV screening is a relatively fast process in patients who present
12
for preoperative appointments. Treatment options approved by the FDA include
13
metronidazole, clindamycin, tinidazole, and secnidazole. Given the prevalence of BV and the
14
risks associated with operating on a woman with untreated BV, women undergoing
15
hysterectomy, surgical abortion, and potentially cesarean delivery should be screened for BV,
16
and those who screen positive should be treated with an appropriate antimicrobial agent.
17 18
Keywords: bacterial vaginosis, clindamycin, metronidazole, secnidazole, surgical site infections,
19
tinidazole
3
1 2
Introduction Bacterial vaginosis (BV) is a common condition among women, with approximately one-
3
third of those between 14 and 49 years of age screening positive for BV.1 A similar proportion
4
of postmenopausal women also screen positive for BV.2 Among women presenting for care, BV
5
is the most prevalent cause of vaginal discharge or malodor; however, most women with BV are
6
asymptomatic.1,3 Beyond the discomfort of BV, the condition is associated with several adverse
7
outcomes. The link between untreated BV and subsequent sexually transmitted infections (STIs)
8
is well established; STIs associated with BV infection include Chlamydia trachomatis, Neisseria
9
gonorrhoeae, Trichomonas vaginalis, and herpes simplex virus infection.4-6 Furthermore,
10
untreated BV is associated with a substantial increase in the risk of HIV acquisition.7,8 Untreated
11
BV also has effects on fertility and pregnancy outcomes, as it has been associated with tubal
12
infertility, and an increased risk of preclinical pregnancy loss, spontaneous abortion, and
13
preterm delivery.9 Moreover, BV increases the risk of gynecologic and obstetric postoperative
14
site infections following cesarean delivery, hysterectomies, and surgical abortions. These
15
infections are associated with a range of negative outcomes: longer duration of hospital stay,
16
use of emergency department resources, hospital readmission, reoperation, and sepsis.10 The
17
aim of this article is to review the literature with regard to the association between BV and
18
gynecologic and obstetric postsurgical infections, as well as provide guidance on pre-operative
19
BV treatment.
20 21
Etiology of BV
4
1
In the National Health and Nutrition Examination Surveys (NHANES), only 16% of
2
women who screened positive for BV reported vaginal symptoms, such as vaginal odor,
3
wetness, and discharge.3 Given the low proportion of women who report signs of BV and the
4
nonspecific nature of the symptoms, dependence on clinical interviews to diagnose BV may
5
miss a large proportion of BV cases.11 Therefore, BV is often underdiagnosed and may go
6
untreated.12 A variety of modifiable factors are associated with an increased risk of BV,
7
including multiple male and female sex partners, a new sex partner, douching, and lack of
8
condom use.13
9
The precise etiology of BV is unclear, but as we gain understanding of the vaginal
10
microbiome, we realize how microbiota play a significant role in the health of the female
11
reproductive tract. While diverse microbial communities are considered a healthy sign in most
12
sites of the human body (ie, the gastrointestinal system), a healthy female reproductive tract is
13
more likely associated with low microbial diversity dominated by one or a few Lactobacillus
14
species.14 Species of Lactobacillus have been historically associated with vaginal health in
15
reproductive-age women due to the direct and indirect protective nature derived from
16
Lactobacillus products, including lactic acid and bacteriocin, which oppose mucus degradation
17
and inhibit pathogens. It is generally agreed that BV occurs when Lactobacillus-dominant
18
vaginal flora are disrupted, reducing the proportion of lactic acid-producing bacteria and
19
increasing the proportion of BV-related bacteria.15,16 In addition, the presence of hydrogen
20
peroxide-producing lactobacilli can prevent the growth of pathogens associated with BV.17
21
Bacteria that are associated with BV include Gardnerella vaginalis, Megasphaera spp,
22
Atopobium vaginae, Dialister spp, Leptotrichia amnionii, Sneathia sanguinegens, 5
1
Porphyromonas asaccharolytica, and Prevotella bivia.16,18 In a systematic review of studies that
2
incorporated at least one molecular technique (sequencing, PCR, DNA fingerprinting, or DNA
3
hybridization), lactobacilli-dominated vaginal micro-environments were associated with vaginal
4
health.
5
Ethnicity is a major intrinsic factor known to be significantly associated with variance in
6
community composition, with Caucasian and Asian women displaying a significantly greater
7
prevalence of Lactobacillus spp dominant microbiota compared with Hispanic and black
8
women.14,19 These differences may be due to genetic factors that influence mucosal immunity
9
or metabolic pathways, which result in preferential conditions for particular species, as well as
10
variation in practices such as vaginal douching, which is twice as common in black women
11
compared with Caucasians.14,20
12 13 14
Benefits of BV Pretreatment of Surgical Site Infections Surgical site infections that complicate procedures performed by obstetricians and
15
gynecologists involve the ascending spread of microorganisms in the vagina and cervix to the
16
upper genital tract.21 Surgical sites include the endomyometrium, incised at the time of
17
cesarean; the vaginal cuff and paravaginal tissues, incised at the time of hysterectomy; or the
18
endometrium, evacuated with uterine curettage in treating disorders of early pregnancies
19
(incomplete, missed, or elective abortion). BV microorganisms are commonly isolated from the
20
surgical sites of women with a surgical site infection.22,23 Moreover, the concentration of
21
potential bacterial pathogens in the vagina of women with BV is increased by 100- to 1000-
6
1
fold.24 Studies evaluating perioperative treatment of BV suggest that identifying women with
2
BV prior to surgery can lead to a substantial reduction in postoperative infections.25,26
3
With regard to pregnancy, BV has been shown to increase the risk of developing
4
intrapartum chorioamnionitis, which is an established risk factor for postpartum endometritis.27
5
Additionally, BV is associated with postcesarean endometritis with the isolation of BV
6
microorganisms in the endometrial cavity of these patients.23 Among women undergoing
7
cesarean delivery, the preoperative administration of intravaginal metronidazole gel reduced
8
the risk of postcesarean endometritis by 58%.28 In another study, perioperative ampicillin plus
9
metronidazole decreased the rate of infections for women undergoing cesarean delivery (38%
10 11
vs 15%) relative to perioperative benzylpenicillin, which does not effectively treat BV.29 In an analysis of 134 patients who underwent abdominal hysterectomy, the rate of
12
vaginal-cuff cellulitis or abscess was significantly higher in patients with preoperative BV
13
compared with patients without BV (34% vs 11%).22 Similar rates of posthysterectomy infection
14
were reported in other studies, with rates of vaginal-cuff and deep infections ranging from 25%
15
to 34% – an approximately 3-fold increase in risk relative to populations without BV.10,22,30 The
16
association of BV with postoperative infections is further supported by the isolation of BV-
17
related organisms such as G. vaginalis from patients with posthysterectomy cuff infections.22
18
Treatment of BV prior to hysterectomy was also beneficial. In a randomized trial, preoperative
19
treatment with metronidazole resulted in a significantly lower rate of vaginal-cuff infections in
20
women with BV who underwent hysterectomy compared with those who did not receive
21
treatment for BV (0% vs 36%; P <.05).31 In a larger nationwide study, preoperative treatment
22
with antibiotics for BV reduced the rate of severe postoperative infections among women with 7
1
BV by 73%.10 Additionally, compared with placebo, prophylactic intravenous metronidazole in
2
women undergoing abdominal hysterectomy reduced the rate of postoperative infections (12%
3
vs 6%) and the duration of hospitalization (9 vs 8 days).32 In the study of perioperative ampicillin
4
plus metronidazole mentioned above, infections related to hysterectomy also decreased (20%
5
vs 3%) relative to perioperative benzylpenicillin.29
6
Screening patients for BV prior to hysterectomy and treating patients who screen
7
positive regardless of symptoms is a cost-effective option for preventing vaginal-cuff infections.
8
In a study of preoperative screening for BV, the costs of the following presurgical options for
9
women undergoing hysterectomy were compared: testing all patients for BV and treating if
10
positive, treating all patients for BV, and neither testing nor treating patients for BV.33 Treating
11
all patients with metronidazole was associated with the lowest modeled rate of cuff infections
12
(4%) and the lowest cost ($593).33 Testing all patients but treating only positive patients was
13
similarly cost-effective ($623), with an acceptable rate of cuff infections (4%).33 Although
14
treating all patients with metronidazole was modestly more cost-effective in this study,
15
treatment following screening would appear to be a more practical option. Single-dose
16
metronidazole added to cefazolin as antibiotic prophylaxis does not effectively treat BV; a
17
multi-dose regimen of metronidazole is recommended. Moreover, with a prevalence of up to
18
30%, the majority of preoperative patients will not require antibiotic therapy for BV prior to
19
surgery.3
20
Preoperative treatment for BV may also reduce the risk of infection in women post-
21
termination of early pregnancy. In one study, the risk of postabortal endometritis was elevated
22
6-fold among women with preoperative BV.34 In randomized controlled trials of women with BV 8
1
undergoing first-trimester abortions, infection rates were 3- to 4-fold lower among women who
2
received preoperative metronidazole or clindamycin.25,26 Perioperative treatment with
3
metronidazole has also been reported as an effective option for women with BV undergoing
4
abortion, resulting in a risk reduction of approximately one-half for postprocedural upper
5
genital tract infections.35 In a recent retrospective study in Sweden with longitudinal follow-up,
6
women undergoing voluntary abortion between 2008 and 2015 were screened for chlamydia,
7
gonorrhea, mycoplasma, and BV prior to the abortions. Abortion complications,
8
bleeding, infection, or incomplete abortion were assessed in women who came to the
9
gynecological clinic within 30 days after the procedure. Women who tested positive for one or
10
several bacteria when screened and who received antibiotics experienced almost the same rate
11
of postabortal infections compared with women who tested negative upon screening.36 While
12
approximately 15% of the study participants screened positive for BV, the study was not
13
specific for BV.36 In this study, preabortion screening with subsequent antibiotic treatment in
14
women who tested positive for certain bacteria appeared to decrease the number of
15
postabortion infections. Nevertheless, the data are still not clear as to which bacteria are
16
causing the infections. In a recent prospective observational study in Finland, 5279 women
17
undergoing hysterectomy for benign indications were given cefuroxime and/or metronidazole.
18
Cefuroxime appeared to be effective in prophylaxis against infections while metronidazole
19
appeared to be ineffective, with no additional risk-reductive effect when combined with
20
cefuroxime.37
21
The available evidence suggests a possible benefit of screening and treating patients for
22
BV prior to labor, hysterectomy, and surgical abortion. In the American College of Obstetricians 9
1
and Gynecologists (ACOG) guidelines for the prevention of infection after gynecologic
2
procedures, it was noted that preoperative screening and treatment for BV “can be considered”
3
before hysterectomy.38 Given similar evidence linking BV to intrapartum chorioamnionitis and
4
postcesarean endometritis,23,27,39 screening for BV at the 35- to 37-week group B streptococcus
5
culture visit and treating those with BV should also be considered. In the absence of guidance
6
from professional societies, many clinicians may be unaware of the risks of BV during surgical
7
interventions and the potential benefits of BV treatment. In the era of “zero tolerance” for
8
surgical site infections, preoperative screening for and treatment of BV may allow an additional
9
incremental decrease in surgical site infections.
10 11 12
BV Treatment Options BV can be treated with a variety of oral and intravaginal antibiotic options (Table 1). In
13
the 2015 guidelines on sexually transmitted disease management, the CDC recommends BV
14
treatment with oral metronidazole 500 mg twice a day for 7 days, intravaginal metronidazole
15
gel 5 g once a day for 5 days, or intravaginal clindamycin cream 5 g at bedtime for 7 days.13 The
16
alternative regimens recommended by the CDC are oral tinidazole 2 g once daily for 2 days, oral
17
tinidazole 1 g once daily for 5 days, oral clindamycin 300 mg twice daily for 7 days, or
18
intravaginal clindamycin ovules 100 mg at bedtime for 3 days; however, the CDC noted that
19
there are limited data for the efficacy of the alternative options.13 The CDC-recommended
20
regimens for BV management have been shown to have roughly equivalent effectiveness within
21
trials, but differences in cure definitions and follow-up times limit comparisons across trials.40
10
1
Shorter courses of treatment are often beneficial to ensure patient adherence, and may
2
be particularly useful in the setting of preventing surgical site infections. However, shorter
3
courses of treatment may not be as effective as longer ones. For example, the CDC-
4
recommended 2-day option of tinidazole 2 g is not as effective as a 5-day course of tinidazole 1
5
g. In a randomized controlled trial, 5 days of tinidazole 1 g resulted in a significantly better cure
6
rate compared with 2 days of tinidazole 2 g (37% vs 27%; P<0.001).41 Although a single oral
7
dose of metronidazole 2 g has been shown to have good efficacy with a 90% cure rate, it is
8
important to note that cure was defined as the absence of clue cells and the absence of at least
9
2 other BV-associated symptoms assessed on day 8, which is a short follow-up period relative to
10 11
other studies discussed here. Furthermore, adverse events are more common at this dose.42 Clindamycin 2% and metronidazole gel 1.3% (not to be confused with MetroGel vaginal
12
0.75%) are FDA-approved single-dose intravaginal options.43,44 It is important to note that the
13
treatment regimens reviewed have not necessarily been evaluated in the setting of
14
preoperative treatment measuring the reduction of surgical site infections.
15
A recent addition to the BV therapeutic armamentarium is single-dose treatment with
16
oral secnidazole 2 g, which was approved by the FDA for the treatment of BV in 2017.45 In a
17
randomized controlled trial, single-dose secnidazole 2 g significantly improved clinical cure
18
rates compared with placebo (53% vs 19%; P<0.001).46 Of note, clinical cure in this phase 3 trial
19
required that patients meet the following criteria at study days 21 to 30, which are more
20
stringent compared with clinical trials performed in earlier years: normal vaginal discharge,
21
negative whiff test, and less than 20% of clue cells of total epithelial cell count.46 When
22
compared with a 7-day oral metronidazole regimen, a single dose of secnidazole 2 g resulted in 11
1
noninferior clinical cure rates at day 21 (60% vs 60%).47 In an open-label study evaluating
2
safety, common treatment-related adverse events included vulvovaginal candidiasis (5%),
3
nausea (4%), and bad taste (3%).48
4 5 6
Managing BV Prior to Surgery Given the asymptomatic status of the majority of women with BV and the other
7
associated difficulties with diagnosing BV,3 screening women for BV prior to obstetric and
8
gynecologic surgeries can contribute to further reducing postoperative infections in a safe and
9
cost-effective manner. Evaluating patients with the Amsel criteria is simple, quick, and
10
inexpensive, and can be performed at preoperative appointments. Preoperative BV screening
11
should be considered before hysterectomy, surgical abortions, and in the late third trimester of
12
pregnancy. To ensure informed decision-making, a discussion about the risks of postoperative
13
infections should be a standard part of patient counseling prior to obstetric and gynecologic
14
surgeries.
15
Preoperative management of BV should prioritize effectiveness, adherence, and, in
16
some cases, duration of treatment. One of the conventional advantages of single-dose therapy
17
is the virtually assured adherence of patients. For preoperative treatment of BV, there is the
18
added advantage of quickly treating BV prior to a scheduled surgery date. Single-dose
19
treatment options (ie, oral secnidazole 2 g, oral metronidazole 2 g, intravaginal metronidazole,
20
or intravaginal clindamycin) should be considered for patients who have preoperative
21
appointments that are less than a week from surgery. If the preoperative appointment is 7 days
22
or more before the date of surgery, clinicians might elect to use one of the multidose regimens 12
1
(see Table 1). For all patients, decisions should be made based on likelihood of adherence,
2
patient preferences for route of administration and dosing, and risk-benefit profiles.
3 4 5
Conclusion Women with BV are at increased risk of adverse pregnancy outcomes and infectious
6
complications following obstetric and gynecologic surgery. The diagnosis of BV is quick,
7
inexpensive, and simple with the use of microscopy or available point-of-care testing. Screening
8
for BV is needed given that it is asymptomatic in most women. Treatment options allow
9
preoperative eradication of BV and may further contribute to lowering the risk of surgical site
10
infections. Future prospective study is needed to clarify the impact of this cost-effective
11
intervention in further reducing the number of women whose procedures will be complicated
12
by surgical site infection.
13 14 15
13
1 2 3 4
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1
Table 1. Approved treatment regimens for bacterial vaginosis13 Drug formulation
Dose
Frequency and duration
Metronidazole
500 mg
BID for 7 days
Metronidazole
2g
Single dose
Tinidazole
1g
QD for 5 days
Tinidazole
2g
QD for 2 days
Clindamycin
300 mg
BID for 7 days
Secnidazole
2g
Single dose
Metronidazole gel 0.75%
5 g (one full applicator)
QD for 5 days
Metronidazole gel 1.3%
5 g (one full applicator)
Single dose (at bedtime)
Clindamycin cream 2%
5 g (one full applicator)
QD (at bedtime) for 7 days
Clindamycin cream 2% ER
5 g (one full applicator)
Single dose
Clindamycin ovule
100 mg
QD (at bedtime) for 3 days
Oral
Intravaginal
2 3
[Table footnote]
4
BID, twice daily; ER, extended release; QD, once daily.
21