Infections caused by anaerobic bacteria are common, and may be serious and life-threatening. Anaerobes predominant in the bacterial flora of normal human skin and mucous membranes, and are a common cause of bacterial infections of endogenous origin. Infections due to anaerobes can evolve all body systems and sites. The predominate ones include: abdominal, pelvic, respiratory, and skin and soft tissues infections. Because of their fastidious nature, they are difficult to isolate and are often overlooked. Failure to direct therapy against these organisms often leads to clinical failures. Their isolation requires appropriate methods of collection, transportation and cultivation of specimens. Treatment of anaerobic bacterial infection is complicated by the slow growth of these organisms, which makes diagnosis in the laboratory only possible after several days, by their often polymicrobial nature and by the growing resistance of anaerobic bacteria to antimicrobial agents.

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Female Genital Tract Infection Caused by Anaerobes


Polymicrobial aerobic-anaerobic female genital tract infections include vulvovaginitis, vulvovaginal pyogenic infections (abscesses of Bartholin’s and Skene’s glands, infected labial inclusion cysts, labial abscesses, furunculosis, and hidradenitis ), endometritis, pyometritis, salpingitis, pelvic inflammatory disease (PID), and tuboovarian and pelvic abscess.



Microbiology & Pathogenesis


With only a few exceptions the pathogens involved in gynecologic infections reflect the normal vaginal and cervical flora. This flora is complex and includes obligate anaerobes such as Gram negative bacilli, Peptostreptococcus spp., Enterbacteriaceae, and aerobic and microaerophilic streptococci.1 Variations in cervical-vaginal flora are related to the effects of age, pregnancy, and menstrual cycle.1

Anaerobes can be cultured in 50% to 90% of females with a variety of genital infections and are the exclusive isolates in 20% to 50%. Obligate anaerobes are particularly common in closed space infections, such as tubo-ovarian and vulvovaginal abscesses.
Most infections are polymicrobial aerobic-anaerobic. The commonest anaerobes are Gram-negative bacilli (especially Prevotella bivia and Prevotella disiens) and anaerobic cocci. The frequent aerobes are Enterobacteriaceae, ( mainly E. coli ) and aerobic or microaerophilic streptococci. 2 Sexually acquired infections include Neisseria gonorrhoeae, Gardnerella vaginalis, Trichomonas vaginalis, Chlamydia trachomatis, herpes simplex, and Condyloma accuminata.
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SPECIFIC INFECTIONS




VULVOVAGINITIS


Pathogenesis & Microbiology

Vulvovaginitis (VV) is considered to be a disturbance in vaginal flora rather than a true infection. The healthy, normal vaginal pH of 3.8 to 4.2 is largely dependent upon the presence of Lactobacillus acidophilus, that produces lactic acid and hydrogen peroxide.3 Loss of dominance of lactobacillus results in overgrowth of facultative and obligate symptom causing anaerobes.

In both specific or nonspecific VV, changes occur in the normal vulvovaginal flora that may induce inflammation. The specific organisms that cause infection in the prepubertal female are often respiratory, enteric, or sexually transmitted pathogens. The adolescent and adult are more likely to have VV with a specific etiology. The three most common types include nonspecific VV, or VV caused by candida, or trichomonas. Sexually acquired infections include Neisseria gonorrhoeae, G. vaginalis, Trichomonas vaginalis, Chlamydia trachomatis, herpes simplex, Mycoplasma hominis and Condyloma accuminata.

Bacterial vaginosis is a synergistic infection caused by a complex alteration in the microbial flora, with 100- to 1000-fold increase in the number of G. vaginalis organisms as well as anaerobic bacteria, a decrease in lactobacilli, and an increase in organic acids produced by the abnormal flora.3 An association was found between bacterial vaginosis and the development of acute PID. The microorganisms associated with bacterial vaginosis include anaerobes such as P bivia, other Prevotella spp,10 butyrate-producing Peptostreptococcus spp., a comma-shaped bacteria,12 and Morbiluncus curtsii, a curved motile anaerobic rod.3

Bacterial vaginitis is characterized by the presence of a gray to white homogenous thin discharge adherent to the vaginal wall, vaginal fluid pH greater than 4.5, a positive whiff test, and the presence of clue cell in 20% of all vaginal epithelial cells.


Management

Treatment attempts to restore the vaginal ecosystem by suppressing the anaerobic component and restoring normal conditions. Therapy of specific VV is prescribed according to offending pathogens with either intravaginal cream or oral agents. Two intravaginal anti-anaerobic preparations are currently available, clindamycin (2%) vaginal cream (qd) or metronidazole gel (0.75%) (bid).4 An alternative is metronidazole administered as a single dose (2 g) or 250 mg po tid or 500 mg po bid for 7 days.  Ampicillin, although less effective, is an alternative drug during pregnancy.




VULVOVAGINAL PYOGENIC INFECTIONS

Vulvovaginal pyogenic infections include abscesses of Bartholin’s and Skene’s glands, infected labial inclusion cysts, labial abscesses, furunculosis, and hidradenitis. N. gonorrhoeae is responsible for approximately 10% of these infections. The majority of nonvenereal abscesses are caused by anaerobic bacteria. 5

In diabetics the inflammation can extend to deeper structures of the perineum, the lower extremities, or back and cause extensive necrosis.


Management

      Therapy consists of surgical drainage and antimicrobials.24 Initial agents should be effective against both aerobic and anaerobic bacteria of vaginal-cervical origin, and should include agents effective against N. gonorrhoeaeS. aureus, and Enterobacteriaceae. A pencillinase-resistant penicillin ( i.e. oxacillin), a cephalosporin plus an fluoroquinolones or an aminoglycoside is an adequate combination. Coverage against methicilin resistant S. aureus may be indicated. Antimicrobials effective against beta-lactamase producing anaerobic bacteria include metronidazole, chloramphenicol, clindamycin, a carbapenem, cefoxitin, and the combination of a penicillin and a beta-lactamase inhibitors.



ENDOMETRITIS AND PYOMETRA

           Endometritis occurs when bacteria invade the uterine cavity, and pyometra develops when pus is collected within the uterus. Regardless of the etiology, anaerobes are predominant and the most frequent anaerobic isolates were anaerobic streptoccocci and Gram negative bacilli.

CT of Post partum endometritis


Management

Pyometra is an abscess and treated promptly and vigorously with drainage of the uterine cavity followed by curettage to debride necrotic tissue. The most serious fatal complication is spread of organisms from the uterus into the blood.1,20

Appropriate specimens for cultures should be obtained prior to initiation of therapy. Antibiotics effective against aerobic and anaerobic bacteria should be given.  Combined therapy with an aminoglycoside or a third-generation cephalosporin and an agent against anaerobes (clindamycin, metronidazole, chloramphenicol, cefoxitin) or single-agent therapy with a carbapenem will be adequate in most patients.




ACUTE SALPINGITIS AND PELVIC INFLAMMATORY DISEASE (PID)



PID often begins with cervical infection caused by C trachomatisN gonorrhoeae, or both. Acute salpingitis and PID are extension of that infection through a transient endometritis or via lymphatic spread. Multiple aerobes and anaerobes species that ascended from the vaginal flora can be isolated. Chlamydiae and mycoplasmae also have been implicated. The predominant anaerobes were gram negative bacilli (especially Prevotella bivia and Prevotella disiens) and anaerobic cocci. The predominant aerobes are Enterobacteriacea , N. gonorrhoeae , Streptococcus spp., and S. aureus . 6,7



Salpingitis



Diagnosis

Acute PID causes fever, increased vaginal discharge, chills, malaise, anorexia, nausea, and severe bilateral lower abdominal pain. Adynamic ileus may be present in pelvic peritonitis. Pelvic examination reveals a purulent cervical discharge and exquisite cervical motion tenderness. The adnexal regions are tender and thickened, and an adnexal or cul-de-sac mass may be palpable. Criteria for clinical diagnosis of PID were published by the Center for Disease Control (CDC)8,9. The CDC recommends the use of three minimum criteria and optional, additional criteria for the diagnosis of PID.
  • endometrial biopsy with histopathologic evidence of endometritis;
  • transvaginal sonography or magnetic resonance imaging techniques showing thickened, fluid-filled tubes with or without free pelvic fluid or tubo-ovarian complex, or doppler studies suggesting pelvic infection (e.g., tubal hyperemia); and
  • laparoscopic abnormalities consistent with PID.
PID must be differentiated from other acute lower abdominal processes such as acute appendicitis, pelvic endometrosis, ovarian tumors, rupture of an ovarian cyst, or a ruptured ectopic pregnancy. Visual confirmation of tubal inflammation can be done by colposcopy and laparoscopy. Ultrasonography can reveal fluid in the uterus or cul-de-sac, increased adnexal volume, and hydrosalpinx. 

Cultures are only valuable when they are obtained by colposcopy, laparoscopy, or culdocentesis. The material should be Gram stained and cultured for aerobic and anaerobic bacteria.


Pelvic Inflammatory disease



Management

Salpingitis and PID are managed primarily with antimicrobials. Salpingitis can be treated by penicillin plus probenecid, ampicillin, a quinolone or tetracycline. Surgical intervention may be required if the patient fails to respond to medical therapy. Severely ill patients should be admitted to the hospital, particularly if an adnexal mass or peritonitis is present.
Early treatment of PID reduces the damage to the fallopian tubes7 and decrease incidence of serious sequela. Antimicrobials should eradicate both aerobic and anaerobic bacterial pathogens as well as N. gonorrhoeae and C. trachomatis. Agents effective against the anaerobes are metronidazole, clindamycin, cefoxitin, a carbapenem, and the combination of a penicillin and a beta-lactamase inhibitor. Antimicrobials effective against the Gram-positive aerobic pathogens, N. gonorrhoeae and C. trachomatis are macrolides (e.g. azithomycin ) and tetracyclines. Aminoglycosides, quinolones or third generation cephalosporins are effective against Gram-negative enterics.

There is no single agent that can provide such coverage. Therefore, combination therapy is advocated. A combination therapy that is often used is cefoxitin and doxycycline. While cefoxitin provides adequate coverage against anaerobic Gram-negative bacilli, doxycycline is directed at N. gonorrhoeae and C. trachomatis. The combination of clindamycin and gentamicin also provides coverage for anaerobic Gram-negative bacilli, and C. trachomatis. The combination of metronidazole and a macrolide is acte against anaerobic Gram-negative bacilli, (metronidazole) and against Ctrachomatis and N. gonorrhoeae ( macrolide). When sexually transmitted pathogens are involved, sexual partners need to be treated.

The CDC recommends regimens for inpatient treatment and outpatient treatment.9 Parenteral treatment is recommended for those with mild or moderate severity. Regimen A uses cefotetan or cefoxitin plus doxycycline. Parenteral Regimen B uses clindamycin plus gentamicin. Oral therapy can be initiated within 24 hours of clinical improvement. It can be ceftriaxone (IM) or cefoxitin (IM) plus doxycycline with or without metronidazole to conclude a 14-day course.



Parenteral Treatment

Recommended Parenteral Regimen A

Cefotetan 2 g IV every 12 hours
   OR
Cefoxitin 2 g IV every 6 hours
   PLUS
Doxycycline 100 mg orally or IV every 12 hours



Recommmended Parenteral Regimen B

Clindamycin 900 mg IV every 8 hours
   PLUS
Gentamicin loading dose IV or IM (2 mg/kg of body weight), followed by a maintenance dose (1.5 mg/kg) every 8 hours. Single daily dosing may be substituted.



Alternative Parenteral Regimens

Levofloxacin 500 mg IV once daily*
   WITH OR WITHOUT
Metronidazole 500 mg IV every 8 hours
   OR
Ofloxacin 400 mg IV every 12 hours*
   WITH OR WITHOUT
Metronidazole 500 mg IV every 8 hours
   OR
Ampicillin/Sulbactam 3 g IV every 6 hours
    PLUS
Doxycycline 100 mg orally or IV every 12 hours




Oral Treatment



Recommended Regimen A

Levofloxacin 500 mg orally qd for 14 days*
   OR
Ofloxacin 400 mg bid for 14 days*
   WITH OR WITHOUT
Metronidazole 500 mg orally bid for 14 days




Regimen B

Ceftriaxone 250 mg IM in a single dose
   PLUS
Doxycycline 100 mg orally bid for 14 days
   WITH OR WITHOUT
Metronidazole 500 mg orally bid for 14 days
   OR
Cefoxitin 2 g IM in a single dose and Probenecid, 1 g orally administered concurrently in a single dose
   PLUS
Doxycycline 100 mg orally bid for 14 days
   WITH OR WITHOUT
Metronidazole 500 mg orally bid for 14 days
   OR
Other parenteral third-generation cephalosporin (e.g., ceftizoxime or cefotaxime)
   PLUS
Doxycycline 100 mg orally bid for 14 days
   WITH OR WITHOUT
Metronidazole 500 mg orally bid for 14 days
Alternative Oral Regimens
If parenteral cephalosporin therapy is not feasible, use of fluoroquinolones (levofloxacin 500 mg orally once daily or ofloxacin 400 mg twice daily for 14 days) with or without metronidazole (500 mg orally twice daily for 14 days) may be considered if the community prevalence and individual risk of gonorrhea is low.

Oral therapy can be considered for women with mild-to-moderately severe acute PID. Patients with an intrauterine device (IUD) have a higher incidence of acute salpingitis.10 Unilateral adnexal infection is frequent, and severe. Additionlly, Actinomyces infections generally are associated with this form of contraception.



Complications

These include peritonitis, recurrent exacerbations, tubo-ovarian abscess, sterility, chronic pain, and dysfunctional bleeding.



TUBOOVARIAN AND PELVIC ABSCESS


Pathogenesis & Microbiology

Tuboovarian abscess (TOA) is a consequence of salpingitis, acute or chronic PID, endometritis, pyelonephritis, uterine fibroids, and pelvic area malignancy. Most pelvic abscesses are polymicrobial with preponderance of anaerobic bacteria, such as Gram negative bacilli (especially Prevotella bivia and Prevotella disiens), anaerobic cocci and Clostridium spp. 2



CT of Tuboovarian abscess






Diagnosis

Patients commonly present with lower abdominal pain or an adnexal mass(es). Fever and leukocytosis may be absent. Ultrasound, CT, MRI, laparoscopy, or laparotomy can confirm the diagnosis.11 TOA may be unilateral or bilateral, regardless of IUD usage.
Rupture of a TOA causes severe pain, chills, fever, and signs of progressing peritonitis. Diarrhea may occur early but ceases as the peritonitis worsens. The infection may spread to cause subphrenic abscesses.


CT of Pelvic abscess



Management

Rapid diagnosis of such an abscess is the key to a successful outcome. Choice of antimicrobials include parenteral clindamycin, cefoxitin, or metronidazole in combination with an aminoglycoside or single-agent therapy with a carbapenem or a beta-lactamase inhibitor plus a penicillin. If no clinical response occurs after 48 to 72 hours or if the abscess enlarges, sonographiclly guided aspiration or surgery is indicated.12 Surgery is also necessary with a TOA rupture.



REFERENCES
1. Larsen, B.,  Galask, R.P.: Vaginal microbial flora and theoretic relevance. Obstet. Gynecol. 55(suppl):100-13, 1980.
2. Brook, I.: The role of beta-lactamase-producing bacteria in obstetrical and gynecological infections. Gynecol Obstet Invest. 32:44–50, 1991.
3.Sobel, J.D.: Nontrichomonal Purulent Vaginitis: Clinical Approach.
Curr Infect Dis Rep.;2:501-505, 2000.
4. Schmitt, C., Sobel, J.D., Meriwether, C.: Bacterial vaginosis: Treatment with clindamycin cream versus oral metronidazole. Obstet Gynecol 79:1020–1023, 1992.
 5. Brook, I.: Anaerobic bacteria in suppurative genitourinary infections. U. Urol. 141:889–93, 1989.
6. Soper, D.E., BrockwellN.J.Dalton, H.P., Johnson, D.: Observations concerning the microbial etiology of acute salpingitis. Am J Obstet Gynecol 170:1008–14, 1994.
7. Ross J., Pelvic inflammatory disease. BMJ. ;322: 658-9. 2001.
8. Gaitán H, Angel E, Diaz R, Parada A, Sanchez L, Vargas C. Accuracy of five different diagnostic techniques in mild-to-moderate pelvic inflammatory disease. Infect Dis Obstet Gynecol ;10:171–80, 2002.
10. Beerthuizen, R.J.: Pelvic inflammatory disease in intrauterine device users. Eur J Contracept Reprod Health Care 1:237–43, 1996.
11. Tukeva, T.A., Aronen, H.J., Karjalainen, P.T., Molander, P., Paavonen, T., Paavonen, J.: MR imaging in pelvic inflammatory disease: comparison with laparoscopy and US. Radiology 210:209–16, 1999.
12. Caspi, B., Zalel, Y., Or, Y., Bar Dayan, Y., Appelman, Z., Katz, Z.: Sonographically guided aspiration: an alternative therapy for tubo-ovarian abscess. Ultrasound Obstet Gynecol 7:439–42, 1996.