Aerobic Vaginitis Infromation

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Aerobic Vaginitis:

Abnormal Vaginal Flora That Is Distinct From Bacterial Vaginosis.

Aerobic vaginitis (AV) is  a state of abnormal vaginal flora that  is  distinct from  the  more common bacterial vaginosis (BV) (Table 1). AV is caused by a displacement of the healthy vaginal Lactobacillus species with aerobic pathogens such as Escherichia coli, Group B Streptococcus (GBS), Staphylococcus aureus, and Enterococcus faecalis that  trigger  a localized  vaginal  inflammatory  immune response.  Clinical signs and symptoms include  vaginal inflammation, an itching or burning sensation, dyspareunia, yellowish discharge, and an increase in vaginal pH > 4.5, and inflammation  with leukocyte infiltration.  (1)Severe, persistent, or chronic forms of AV can also be referred to as desquamative inflammatory vaginitis (DIV). (2, 3)

BV is  a common vaginal disorder associated with theovergrowth  of  anaerobic  bacteria,  a  distinct  vaginal malodorous discharge, but is not usually associated with a strong vaginal inflammatory immune response.  Like AV,BV also includes an elevation of the vaginal pH > 4.5 and a depletion of healthy Lactobacillus species. BV is treated with traditional metronidazole therapy that targets anaerobic bacteria. However, approximately 10% to 20% of women diagnosed with BV and treated with metronidazole will fail

to respond to therapy at one week and will experiencepersistent symptoms. (4, 5) It is believed that a subset of these patients may have been misdiagnosed and actually suffer from AV, which requires an antibiotic therapy withintrinsic activity against specific aerobic bacteria. AV has been implicated in  complications of pregnancy such as ascending  chorioamnionitis,  premature  rupture  of  the membranes, and preterm delivery.

Epidemiology

In a study of 631 patients attending routine prenatal care from a vaginitis clinic, 7.9% had moderate to severe AV signs and symptoms and 6% had ‘full-blown’BV. (1)
In a study of 3,000 women, 4.3% were found to have severe AV, also called DIV. Furthermore, 49.5% of the women with DIV were peri- or postmenopausal. A reported hypothesis is that a drop in estrogen my trigger the development of AV in the aforementioned menopausal women, as well as postpartum nursing women. (3)

Clinical Characteristics Bacterial Vaginosis  Aerobic Vaginitis (1)Lactobacilli Displaced DisplacedPathogen Gardnerella vaginalis, Atopobium vaginae, Megasphaera species, BVAB2Escherichia coli, Group B Streptococcus, Staphylococcus aureus, Enterococcus faecalisVaginal epithelial inflammation None Present Elevation of pro-inflammatory cytokines (IL-1?, IL-6, IL-8) Moderate elevation High elevation Immune reaction (cytotoxic leukocyte) Non-reactive Reactive pH [Normal = 3.8 – 4.2]T= 4.2-4.5
BV >4.5
> 4.5; usually >6
Shed vaginal epithelial cells Clue cells Parabasal cells
Vaginal discharge characteristic White, homogenous   Yellowish
10% KOH Whiff Test (fishy amine odor) Positive Negative
Treatment
Metronidazole b
Clindamycin b
Kanamycin ovule. (5)
2% clindamycin topical. (3)
Fluoroquinolones are reported to have clinical
success. (5)
GBS is uniformly sensitive to penicillin, ampicillin,
amoxicillin, amoxicillin/ clavulanic acid. (7)
E. faecalisis traditionally treated with ampicillin. (8)
Table 1. AComparison of Bacterial Vaginosis and Aerobic Vaginitis.References are provided for treatment information; Fluoroquinolones, such as ciprofloxacin, ofloxacin, and levofloxacin, are contraindicated in pregnant women. Levofloxacin has improved efficacy against Streptococci compared to ciprofloxacin. T= Transitional.

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In a more recent study of 215 women, 19.1% were found to  have  ‘common  vaginitis’  caused  by  BV,  vulvovaginal candidiasis (VVC), or trichomoniasis (TV), whereas 12.6% were found to have ‘inflammatory vaginitis’ (IV). Of the IV group,  77.8%  were characterized  as  having  DIV.  (11)  In fact, 42.9% of the women with DIV were found to be GBS positive, a 5-fold increase over the healthy patients (17.7% positive). (11) This study was similar to an earlier study that found 43% of DIV patients were GBS positive. (2)

Clinical Significance

Patients  with  AV  present  with  distinct  clinical  signs  andsymptoms of abnormal vaginal flora that can be confused with common vaginitis etiologies such as BV, VVC, and TV
(Table 1). AV  is  treated  with  an  antibiotic  course  of  therapy characterized  by  an  intrinsic  activity  against  the  majority of  bacteria  of  fecal  origin,  which  is  different  than  the metronidazole (BV, TV) and antifungal (VVC) antimicrobial agents used to treat common vaginitis (Table 1). In addition to the clinical symptoms of vaginal discharge, dyspareunia,  itching  and  burning  sensation,  and  a strong  inflammatory  response,  AV  was  shown  to  have an  association  with  miscarriage  and  preterm  labor  and delivery. (12, 13, 14) Inflammation derived from the cervicalvaginal environment (vaginitis) and urinary tract infections are known to be associated with triggering labor. Cellular components of GBS such as peptidoglycan and hemolysin and E. colilipopolysaccharide (LPS), known mediators that trigger the inflammatory response, are proposed to be the
causative agents that can initiate preterm labor. Additionally, GBS and E. coliare also major bacterial species involved in neonatal sepsis.

Laboratory Diagnosis

In 2002, Donders et al. published guidelines to characterize the  presence  and  severity  of  aerobic  vaginitis.  This  was based on a similar Nugent scoring method used for bacterial vaginosis determination, which is based on a Gram-stained microscopic evaluation that enumerates specific bacterial morphotypes.  The  presence  and  number  of  the  different bacterial  morphotypes,  such  as  healthy  Gram-positive

such as E. coli, and Gram-positive GBS,S. aureus, and E. faecalis. In a study that measured the minimum inhibitory concentrations  (MIC)  of  prulifloxacin,  ciprofloxacin, ofloxacin,  erythromycin,  doxycycline,  clindamycin, ampicillin,  kanamycin,  and  vancomycin  antibiotics  for  73 vaginal Lactobacillus species,  the  MICs  for  kanamycin,
ciprofloxacin, and ofloxacin were reported to be the greatest and in a concentration range categorized as intermediate or resistant for the AV pathogens.

In a study by Tempera et al., topical kanamycin ovules (100 mg, corresponding to 83 mg of active compound; one ovule per day for 6 days) was shown to have clinical success for the treatment of AV. (7, 8)

Fluoroquinolones,  such  as  ciprofloxacin  and  ofloxacin, have also been reported to have clinical success. These fluoroquinolones  were  reported  to  have  little  effect  on the  normal  flora  allowing  for  a  rapid  recovery.  (8)  A study  measuring  MICs  of  the  four  most  common  vaginal Lactobacillus species  found  that  the  three  healthy
Lactobacillus species, L.  crispatus,  L.  gasseri,  and  L. jensenii,  were  resistant  to  ciprofloxacin,  while L.  iners,  a Lactobacilli not associated with a healthy vaginal flora, was susceptible. (15)

In severe cases of aerobic vaginitis, also referred to as DIV, a successful treatment is 4 to 5 grams of 2% clindamycin cream  daily  for  4  to  6  weeks,  which  has  coverage  for Gram-positive  GBS  and  also  has  been  reported  to
reduce inflammation (5). Although all women experienced improvement using this therapy, it was reported that 32.1% of patients relapsed after 6 weeks and 43.4% of patients
relapsed after 23 weeks. (5) However, GBS vaginitis case reports have demonstrated clindamycin treatment failures due to clindamycin resistant isolates. (16) Approximately
21% (17) to 38% (18) of GBS clinical isolates were reported to be clindamycin resistant; furthermore, clindamycin is not effective against E. coli.

Group B Streptococci are uniformly susceptible to penicillin, ampicillin,  amoxicillin,  amoxicillin-clavulanic  acid,  and cefuroxime  axetil  and  all  were  therefore  reported  to  be appropriate treatment for GBS vaginitis. (19) For penicillin allergic patients, clindamycin is an acceptable alternative. Fluoroquinolones  (levofloxacin)  appear  to  have  efficacy against  isolates  of  Group  B  Streptococci;   resistance  to fluoroquinolones has only recently been reported. (20)
E.  faecalis infections  can  be  treated  with  ampicillin.  The combination  of  ampicillin  and  an  aminoglycoside,  such as gentimicin or spectinomycin, has been shown to have
a  synergistic  effect  on  this  bacterium,  which  is  effective for  severe  infections  (10).  Although  rare,  strains  with ß-lactamase activity or increased MIC for gentimicin can be
treated with ampicillin-sulbactam or high-dose gentimicin, respectively.

 

Pathogenesis

 

 

AV  is  associated  with  an  increase  in  vaginal  pH  (>  4.5), depletion of vaginal healthy Lactobacilli, and an overgrowth of  aerobic  or  facultative  anaerobic  bacteria,  usually  the
Gram-negative bacilli E. colior Gram-positive cocci GBS, and  occasionally S.  aureus and E.  faecalis.  The  high concentration of these aerobic bacteria and the absence of
healthy vaginal Lactobacilli results in triggering the immune system as evidenced by vaginal inflammation, high levels of  proinflammatory  cytokine  production,  recruitment  of
leukocytes,  and  the  generation  of  toxic  leukocytes  and parabasal cells. The patient may present with all or some of these signs and symptoms of AV: yellowish discharge, itching or burning sensation, dyspareunia, absence of the fishy odor (negative amine test) typically associated with BV,  inflammation  (Figure  1),  toxic  leukocyte  infiltration, and  the  presence  of  parabasal  cells  and  naked  rounded vaginal epithelial cells (Figure 2).

Figure  1.  Aerobic  vaginitis  inflammation.

Clinical  pictures adopted  from  Donders et  al,  2002,  demonstrates  patients  with moderate  to  severe  AV.  Discrete  (Patients  A  &  B),  moderate (Patients  C  &  D),  and  severe  ulcerations  (Patients  E  &  F)  are observed along with yellowish discharge and inflammation of the vagina.(1)

Figure  2:  Aerobic  Vaginitis  microscopy.

Images  of  phasecontrast microscopy (x400) adopted from Donders et al., 2002, of vaginal fluid from patients with AV. The vaginal Lactobacilli are displaced with coccoid bacteria (a) or chains of cocci typical for GBS (b). Leukocytes and ‘toxic’ leukocytes (full of lysozymic granules) are present in high numbers (c). Parabasal cells or rounded-up vaginal epithelia, are present (d). (1)
Lactobacilli and anaerobic BV associated Gram-negative and Gram-variable rods, contribute to the overall Nugent Score. A Nugent score of 0 to 3 indicates normal flora, 4 to
6 intermediate flora, and 7 to 10 bacterial vaginosis. The  determination  of  AV  is  also  established  by  an  ‘AV’ score. The score is calculated with the use of high-power
field microscopy to evaluate the presence or absence of healthy Lactobacilli, number of leukocytes, number of toxic leukocytes, type of vaginal flora, and parabasal epithelial cells (Table 2). Here, the presence of the healthy Grampositive Lactobacilli is compared to the presence of aerobic or  facultative  anaerobic  Gram-positive  cocci  (such  as Streptococci,  Staphylococci,  or  Enterococci)  and  Gramnegative bacilli (E. coliand Klebsiella species).

Table  2.  Criteria  for  the  microscopic  diagnosis  of Aerobic  Vaginitis  (AV)  (400X  magnification,  phase contrast microscopy). (1, 14)

The Aerobic Vaginitis (AV) Panel by PCR developed and validated  by  Medical  Diagnostic  Laboratories,  L.L.C. (MDL) utilizes four qPCR reactions to detect the four most common AV-associated bacteria (E. coli, GBS, S. aureus, and E. faecalis). Along with the clinical signs and symptoms (Table  1),  this  assay,  which  correlates  with  the AV  flora discussed in the clinical AV scoring characterization (Table 2), can identify for healthcare providers the AV pathogens involved in the inflammatory vaginitis. (1, 14)

Treatment for Aerobic Vaginitis

The therapy for aerobic vaginitis should include an antibiotic with an intrinsic activity against the majority of bacteria of fecal origin. To increase the safety and compliance, it is best to use a topical formulation which has slow or little absorbency, but is able to maintain the correct pharmaceutical concentration in situ. (8) The optimal treatment includes antibiotics that have little effect on the normal flora, commonly Lactobacillusspecies, while  effectively  eradicating  the  Gram-negative  enterics

3.  Sobel JD, Reichman O, Misra D, Yoo W. 2011. Prognosis and  Treatment  of  Desquamative  Inflammatory  Vaginitis. Obstet Gynecol 117: 850-855.

4.  Wilson J. 2004. Managing recurrent bacterial vaginosis. Sex Transm Infect 80: 8-11.

5.  Larsson  PG. 1992. Treatment  of  bacterial  vaginosis. Int  J
STD AIDS 3: 239-247.

6.  Centers  for  Disease  Control  and  Prevention  (CDC). 2010. Sexually Transmitted Diseases Treatment Guidelines.
MMWR59: 1-110.

7.  Tempera, G, Bonfiglio G, Comparata E, Corsello S, Cianci
A. 2004. Microbiological/clinical characteristics and validation
of topical therapy with kanamycin in aerobic vaginitis: a pilot
study. Int J Antimicrob Agents24: 85-88.

8.  Tempera  G,  Furneri  PM. 010.  Man2 agement  of  Aerobic
Vaginitis. Gynecol Obstet Invest70: 244-249.

9.  Clinical  and  Laboratory  Standards  Institute . 2010. Performance  standards  for  antimicrobial  susceptibility testing:  21st  informational  supplement.  M100-S21,  Vol.  31
(1), Clinical and Laboratory Standards Institute, Wayne, PA.

10.  Arias CA, Contreras GA, Murray BE. 2010. Management
of multidrug-resistant enterococcal infections. Clin Microbiol
Infect 16: 555-562.

11.  Leclair CM, Hart AE, Goetsch MF, Carpentier H, Jensen
JT. 2010.  Group  B  Streptococcus:  Prevalence  in  a  nonobstetric population. J Low Genit Tract Dis14: 162-166.

12.  Donders G, Van Calsteren K, Bellen G, Reybrouck R, Van
den Bosch T, Riphagen I, Van Lierde S .2009. Predictive value  for  preterm  birth  of  abnormal  vaginal  flora,  bacterial
vaginosis  and  aerobic  vaginitis  during  the  first  trimester  of
pregnancy. Br J Obstet Gynecol 116:1315–1324.

13.  Donati L, Di Vico A, Nucci M, Quagliozzi L, Spagnuolo T,
Labianca A, Bracaglia M, Ianniello F, Caruso A, Paradisi
G. 2010. Vaginal microbial flora and outcome of pregnancy.
Arch Gynecol Obstet 281: 589-600.

14.  Donders G, Bellen G, Rezeberga D. 2011. Aerobic vaginitis
in pregnancy. Br J Obstet Gynecol 118: 1163-1170.
15.  De  Backer  E,  Verhelst  R,  Verstraelen  H,  Claeys  G,
Verschraegen G, Temmerman M, Vaneechoutte M. 2006.
Antibiotic  susceptibility  of Atopobium  vaginae.   BMC  Infect
Dis 6: 51.

16.  Honig  E,  Mouton  JW,  van  der  Meijden  WI.  1999. Can Group  B  Streptococci  cause  symptomatic  vaginitis? Infect
Dis Obstet Gynecol 7: 206-209.

17.  Gygax SE, Schuyler JA, Kimmel LE, Trama JP, Mordechai
E,  Adelson  ME. 2006.  Erythromycin  and  clindamycin
resistance  in  Group  B  Streptococcal  clinical  isolates.
Antimicrob Agents Chemother 50: 1875–1877.

18.  Back EE, O’Grady EJ, Back JD. 2012. High rates of perinatal Group  B  Streptococcus  clindamycin  and  erythromycin
resistance  in  an  upstate  New  York  hospital.  Antimicrob
Agents Chemother 56: 739-742.

19.  Clark LR, Atendido M. 2005. Group B Streptococcal vaginitis
in  postpubertal   adolescent  girls. J  Adolescent  Health 36:
437-440.

20.  Wu  HM,  Janapatla  RP,  Ho  YR,  Hung  KH,  Wu  CW,  Yan JJ, et al. 2008. Emergence of fluoroquinolone resistance in group B streptococcal isolates in Taiwan. Antimicrob Agents Chemother 52:1888-1890.

Summary of Treatment

•  Kanamycin ovules (100 mg, corresponding to 83 mg of active compound) one ovule per day for 6 days. (7, 8)
•  2% topical clindamycin. 4 to 5 grams of 2% clindamycin cream  daily  for  4  to  6  weeks.  (desquamative inflammatory vaginitis). (5)
•  Ciprofloxacin or ofloxacin (8, 15).
•  Fluoroquinolones  (ciprofloxacin,  ofloxacin,  and levofloxacin) are contrain dicated in pregnant women.
•  Group  B  Streptococcus  is  uniformly  susceptible to  penicillin,  ampicillin,  amoxicillin,  amoxicillinclavulanic acid, and cefuroxime axetil. Alternatives are clindamycin and levofloxacin.
•  E.  faecalis is  traditionally  treated  with  ampicillin.  A combination  of  ampicillin  plus  an  aminoglycoside (gentimicin  or  spectinomycin)  is  used  for  severe infections. (10)

Clinical Benefits of Testing

MDL offers highly sensitive and specific quantitative RealTime PCR (qPCR)-based assays for the detection of AVassociated  pathogens  utilizing  the OneSwab®platform
Test  182:  Aerobic  Vaginitis  (AV)  by  Real-Time  PCR.
Benefits of this system include:
Real-Time PCR
•     Simple and convenient sample collection.
•     No  refrigeration  is  required  before  or  after collection.
•     Specimen stable for up to five days.
•     Test  additions  are  available  up  to  30  days  after receipt of the specimen.
•     24 – 48 hour turnaround time.
•     High diagnostic specificity and sensitivity.
•     One vial, multiple pathogens.

References

1.  Donders GGG, Vereecken A, Bosmans E, Dekeersmaecker
A,  Salembier  G,  Spitz  B.2002.  Definition  of  a  type  of
abnormal vaginal flora that is distinct from bacterial vaginosis:
aerobic vaginitis. Br J Obstet Gynecol 109: 34-43.
2.  Sobel  JD. 1994.  Desquamative  inflammatory  vaginitis:  a
new subgroup of purulent vaginitis responsive to topical 2%
clindamycin therapy. Am J Obstet Gynecol 171: 1215-1220.