Infections of the female genital tract

Prim Care Clin Office Pract 30 (2003) 193 203 Infections of the female genital tract Soraya Nasraty, MD Department of Family and Community Medicine, University of Louisville, 501 E. Broadway, Suite 240, Louisville, KY 40202, USA Vaginitis Vaginitis is a common gynecologic problem affecting women of all age groups. Vaginitis usually has nonspecific symptoms, and it is necessary to confirm the diagnosis with laboratory tests. The management of vaginitis is mostly empiric, and although vulvovaginitis is frequently the result of infection, it also may have noninfectious causes, such as hypersensitivity, allergic, and chemical reactions and contact dermatitis [1]. Bacterial vaginosis Bacterial vaginosis is a condition of imbalance of the vaginal flora in which the lactobacilli are decreased and bacteria such as Gardnerella vaginalis, Mycoplasma hominis, Ureaplasma urealyticum, and anaerobes are plentiful [2]. Gardner and Dukes first described bacterial vaginosis, its symptoms and signs, and the nature of the discharge and reported the causative organism to be Haemophilus vaginalis, later renamed Gardnerella vaginalis [3]. In the past, treatment of bacterial vaginosis was aimed at eliminating the symptoms of discharge and unpleasant odor. More recent studies, however, point to a link between bacterial vaginosis and endometritis, salpingitis, inflammation of fetal membranes and amniotic fluid during pregnancy [2], and late-term miscarriage. Such associations suggest stronger reasons for treatment than simply to eliminate symptoms. Bacterial vaginosis can be present in sexually active and inactive women [4]. Bacterial vaginosis usually presents with a homogeneous white discharge, vaginal ph range greater than 4.5, and a fishy odor when mixing potassium E-mail address: soraya.nasraty@louisville.edu 0095-4543/03/$ - see front matter Ó 2003, Elsevier Science (USA). All rights reserved. doi:10.1016/s0095-4543(02)00055-6

194 S. Nasraty / Prim Care Clin Office Pract 30 (2003) 193 203 hydroxide with vaginal secretions. The latter symptom is called a positive whiff test. Wet mount technique shows clue cells (vaginal epithelial cells studded with tiny coccobacilli). The decision to treat should take into account a complete evaluation of the patient [4]. Metronidazole (500 mg orally twice daily for 7 days) has been shown to achieve cure rates of 80% to 90% and is as effective as metronidazole administered as 750-mg extended-release tablets once daily for 7 days. Treating with clindamycin, 300 mg orally twice a day for 7 days, or using clindamycin at a dosage of 100 mg intravaginally once at bedtime for 3 days, is also effective [5]. Metronidazole given as a 2-g, single-dose therapy also may be used. Topical treatment with 2% clindamycin cream intravaginally nightly for 7 days or metronidazole 0.75% vaginal gel daily for 5 days is another effective form of treatment. According to current data, it is recommended that women undergoing instrumentation of the upper genital tract and pregnant women be treated even if asymptomatic. There are no supporting data to treat male partners unless there is frequent relapsing disease. Ofloxacin (200 or 300 mg twice a day) may be used for women intolerant to metronidazole or clindamycin [6]. Metronidazole (250 mg orally 3 times a day for 7 days) or clindamycin (300 mg orally twice a day for 7 days) is used for treatment in pregnancy. It is not recommended to use clindamycin cream during pregnancy because of risk of preterm birth [4]. Vulvovaginal candidiasis Candida albicans is the most prevalent causative yeast agent for vulvovaginal candidiasis. The most common symptom is vaginal pruritus followed by vulvar burning, especially with urination or during sexual intercourse. Vaginal discharge is cottage cheese like, with a hyperemic and irritated vulva and edematous vagina. Symptoms tend to recur, probably because of Candidal strains in the rectum that recolonize in the vagina [6]. Predisposing factors for vaginitis are regular sexual activity, oral contraceptives, antibiotics, pregnancy, diabetes mellitus, and tight clothing [1,4,7]. The normal vaginal ph level is usually approximately 4.5. After the addition of 10% to 20% potassium hydroxide solution, a wet-preparation slide mount should demonstrate budding yeast and hyphea even though this test may fail to demonstrate the fungi in 30% to 50% of infected women. In that case, an assessment can be made on the basis of the ph, clinical features, and a negative whiff test [4]. A regular normal saline wet-mount slide also may show the organisms.

S. Nasraty / Prim Care Clin Office Pract 30 (2003) 193 203 195 Topical products used are usually in the antifungal classes of imidazoles (clotrimazole, miconazole, butoconazole, tioconazole, and econazole) or triazoles (terconazole). Cure rates are about the same for a 3- or 7-day regimen. Orally, fluconazole in a single dose of 150 mg is efficacious. Recurrent infections from the same or new strains of candida may benefit from indefinite continuous daily oral treatment with ketoconazole or fluconazole [4]. During pregnancy, only topical azole therapies are to be applied for 7 days. In cases of recurrent vulvovaginal candidiasis, maintenance regimens such as clotrimazole 500-mg vaginal suppositories once weekly or fluconazole as a 100- to 150-mg oral dose once weekly may be used for 6 months [5]. Trichomoniasis The causative organism for trichomoniasis is the protozoan Trichomonas vaginalis. Trichomoniasis is usually sexually acquired and is recovered from 66% to 100% of the female partners of infected men and from 22% to 80% of the male sexual partners of infected women. The infection is self-limited in 20% of the women and 40% of the men. It occasionally can be acquired nonvenereally, and it can survive for several hours in moist environments, including on moist cloths. Transmission by the fingers during mutual masturbation and by the use of sexual toys or shared douche equipment is also possible. It also can be transferred to the neonate during birth [8]. The incidence is highest among women with multiple sexual partners and in patients with high rates of other sexually transmitted pathogens. Patients with T. vaginitis always should be screened for other venereal-acquired pathogens, such as Neisseria gonorrhoeae, Chlamydia trachomatis, or human immunodeficiency virus. Its incidence seems to be decreasing, possibly because of the widespread use of metronidazole for bacterial vaginosis [8]. Symptoms usually include a combination of vaginal discharge (often, but not always, yellow or green) and vulvovaginal irritation. It can be recovered from the urethra and paraurethral glands in 95% of women affected, which explains its association with urinary frequency and dysuria. Approximately 25% of the women carrying trichomonads are asymptomatic. The incubation period for trichomoniasis is 5 to 28 days. In pregnancy, it can be associated with premature labor and low infant birth weight [8]. In fresh preparations, T. vaginalis is motile and pear-shaped and has an average dimension of 10 7 lm. Direct fluorescent antibody staining, latex agglutination, DNA probes, and polymerase chain reaction are other methods of testing. It also may be cultured [8].

196 S. Nasraty / Prim Care Clin Office Pract 30 (2003) 193 203 A single oral dose of 2 g of metronidazole, 250 mg 3 times a day for 7 days, or 500 mg twice a day for 7 days, is a recommended form of treatment. Side effects of metronidazole consist of mild nausea and bad taste. It is not recommended to be taken with alcohol because of a possible resulting disulfiram-like reaction. During pregnancy, women may be treated with 2 g of metronidazole in a single dose. Recurrent infections could be secondary to untreated sexual partners (especially with the single-dose regimen, because some male sexual partners may be completely asymptomatic), noncompliance with medications, increased hepatic inactivation of the drug, and metronidazole resistance. In cases of recurrent infection, it may be prudent to treat for 7 to 14 days [8]. Chlamydia trachomatis Chlamydia trachomatis is the most common sexually transmitted bacterial pathogen in the United States. It can cause urethritis, cervicitis, pelvic inflammatory disease (therefore contributing to ectopic pregnancy [9]), infertility, and chronic pelvic pain. It also increases the risk of acquiring human immunodeficiency virus infection in women. Younger women have increased susceptibility because of the presence of increased cervical columnar epithelium [10]. Chlamydia can persist for a prolonged period in the female genital tract. Seventy percent of women with endocervical infections are asymptomatic or have mild symptoms such as vaginal discharge, bleeding, mild abdominal pain, or dysuria (which could be from urethritis) [11]. In pregnant women, it is associated with adverse pregnancy outcomes, including preterm delivery and postpartum endometritis. Perinatal transmission to infants can cause neonatal conjunctivitis and pneumonia [12]. The following immunologic tests are available to identify chlamydia using endocervical or urethral swabs or urine specimens: direct fluorescent antibody, enzyme immunoassay, nonamplified nucleic acid hybridization, polymerized chain reaction, ligase chain reaction, strand-displacement assay, hybrid caphresystem, and transcription-mediated amplification of RNA. Using urine specimens is a noninvasive way of screening men and women [10]. To treat urogenital chlamydia that has not spread to the upper genital tract, doxycycline is given as 100 mg orally twice daily for 7 days (or

S. Nasraty / Prim Care Clin Office Pract 30 (2003) 193 203 197 erythromycin 500 mg 4 times per day for 7 days as the first alternative). Azithromycin, given as a single 1-g dose, is one of the regimens recommended by the Centers for Disease Control. Ofloxacin at a dose of 300 mg orally twice daily for 7 days or levofloxacin 500 mg orally for 7 days is approved for uncomplicated C. trachomatis infection except in adolescents and pregnant women [11]. Patients should be instructed to abstain from sexual intercourse during treatment for 7 days whether using a single-dose or 7-day regimen. Pregnant women may be treated with erythromycin 250 mg 4 times a day for 14 days or amoxicillin 500 mg 3 times a day for 7 to 10 days if unable to tolerate the standard erythromycin dose. Azithromycin also may be given in a single oral dose of 1 g. Gonorrhea In the United States, an estimated 600,000 new Neisseria gonorrhoeae infections occur yearly. In contrast to men, gonococcal infections among women are often asymptomatic, so it is of the utmost importance that women at high risk for sexually transmitted diseases be screened for gonococcal infection. of infections with N. gonorrhoeae requires identification of the organism at infected sites. The following methods are available: Gram stain, culture, and immunochemical or molecular diagnostic techniques. Patients often are coinfected with C. trachomatis, so it is recommended to treat patients with gonococcal infection with a regimen that is also effective against uncomplicated genital C. trachomatis infection [5]. Recommended regimens include one of the following: Cefixime: 400 mg orally in a single dose Ceftriaxone: 125 mg intra muscularly (IM) in a single dose Ofloxacin: 400 mg orally in a single dose Levofloxacin: 250 mg orally in a single dose Ciprofloxacin: 500 mg orally in a single dose If chlamydial infection is not ruled out, the practitioner also should administer the following: Azithromycin: 1 g orally in a single dose Doxycycline: 100 mg orally twice daily for 7 days

198 S. Nasraty / Prim Care Clin Office Pract 30 (2003) 193 203 Alternative regimens for uncomplicated gonococcal infection include the following: Spectinomycin: 2 g in a single IM dose Single-dose cephalosporin regimens (other than ceftriaxone) Ceftizoxime: 500 mg IM Cefoxitin: 2 g IM in a single dose preceded by probenecid, 1 g orally Cefotaxime: 500 mg IM Single-dose quinolone Gatifloxacin: 400 mg orally Norfloxacin: 800 mg orally Lomefloxacin: 400 mg orally Quinolone-resistant N. gonorrhoeae Quinolone-resistant N. gonorrhoeae infection is becoming increasingly common on the West Coast of the United States and is expected to continue to spread, so it is crucial to monitor antimicrobial resistance [5]. Single-dose quinolone regimens (ciprofloxacin, ofloxacin, and levofloxacin) do not offer any advantage to the above-mentioned cephalosporin regimens. Management of sexual partners Patients should be instructed to refer their sexual partners for evaluation and treatment. Patients are to avoid sexual intercourse until their partner s therapy is completed and until they no longer have symptoms [5]. Pregnancy It is recommended that alternative-regimen cephalosporins be used for treatment of gonorrhea during pregnancy. If the individual cannot tolerate cephalosporins, spectinomycin (2 g IM) should be used [5]. Human papillomavirus infection Infection of the genital tract with human papillomavirus can be asymptomatic or subclinical. Human papillomavirus types 6 and 11 usually cause visible genital warts. Types 16, 18, 31, 33, and 35 have been associated with cervical neoplasia. Genital warts are commonly asymptomatic but can cause pruritus and be painful. Visible genital warts may resolve on their own, remain the same, or increase in size. The goal of treatment is removal of symptomatic warts. There are several modes of treatment and factors that influence the selection

S. Nasraty / Prim Care Clin Office Pract 30 (2003) 193 203 199 of treatment. These factors include wart size, wart number, anatomic site of the wart, wart morphology, patient preference, cost of treatment, convenience, adverse effects, and provider experience [5]. Regimens The recommended regimens for external genital warts are as follows. Patient-applied treatment Podofilox 0.5% solution or gel may be applied with a cotton swab twice daily for 3 days followed by 4 days of no therapy. This regimen may be repeated for 4 days. Imiquimod 5% cream should be applied once at bedtime, 3 times a week for up to 16 weeks. The treatment area should be washed with soap and water 6 to 10 hours after the application [5]. Provider-administered treatment Cryotherapy using liquid nitrogen or cryoprobe is administered by a physician. The application can be repeated every 1 to 2 weeks. Podophyllin resin 10% to 25% is prepared in a compound tincture of benzoin. Each wart is treated with a small amount of this preparation, allowed to air dry, and washed off in approximately 4 hours. can be repeated weekly. Trichloroacetic acid or bichloroacetic acid 80% to 90% is applied to each wart and allowed to air dry. A white frosting will develop on the wart. can be repeated weekly. Surgical removal by curettage, tangential excision, or scissor excision is also an option for removal of external genital warts. Alternative regimens Intralesional interferon and laser surgery are included as options in the removal of genital warts [5]. Cervical warts In treating cervical warts, high-grade squamous intraepithelial lesions must be excluded before treatment is initiated. Vaginal warts The recommended regimens are as follows. Cryotherapy with liquid nitrogen Trichloroacetic acid or bichloroacetic acid (80% 90%) is applied to warts [5].

200 S. Nasraty / Prim Care Clin Office Pract 30 (2003) 193 203 Anal warts The recommended regimens are as follows. Cryotherapy with liquid nitrogen Trichloroacetic acid or bichloroacetic acid (80% 90%) as described previously. The use of imiquimod, podophyllin, or podofilox is not recommended during pregnancy [5]. Genital herpes Genital herpes is a sexually transmitted disease caused by the herpes simplex virus (HSV). Two serotypes have been identified: HSV-1 and HSV- 2. Most cases of recurrent genital herpes are caused by HSV-2 [5]. Persons infected with HSV-2 may be unaware that they are infected, that they are shedding the virus, or that transmission has occurred [5]. There are three types of HSV genital infections: (1) primary infection (initial infection with either HSV-1 or HSV-2 without prior exposure); (2) recurrent infection (reactivation of latent virus); and (3) nonprimary firstepisode infection a first episode with HSV-1 or HSV-2 in a patient with prior exposure to the other viral serotype [5]. Because typical painful vesicular or ulcerative lesions are not always present, clinical diagnosis may be nonspecific and should be confirmed by laboratory testing. The preferred virologic test is isolation of HSV in a cell culture. Herpes simplex virus antigen-detection tests do not distinguish HSV-1 from HSV-2 [5]. Systemic antiviral drugs are the mainstay of treatment. It is of utmost importance, however, to counsel patients regarding sexual and perinatal transmission. Available resources to assist patients and clinicians in counseling of genital herpes are the Centers for Disease Control National STD/HIV Hotline (800-227-8922) and the Web site (http://www.ashastd. org) [5]. Recommended regimens are as follows: First-episode therapies Acyclovir: 400 mg orally 3 times a day for 7 to 10 days Acyclovir: 200 mg orally 5 times a day for 7 to 10 days Famciclovir: 250 mg orally 3 times a day for 7 to 10 days Valacyclovir: 1 g orally twice a day for 7 to 10 days

S. Nasraty / Prim Care Clin Office Pract 30 (2003) 193 203 201 Recurrent-episode therapies (can be administered episodically or continuously to reduce the frequency of occurrences) Episodic Acyclovir: 400 mg orally 3 times a day for 5 days Acyclovir: 200 mg orally 5 times a day for 5 days Acyclovir: 800 mg orally twice a day for 5 days Famciclovir: 125 mg orally twice a day for 5 days Valacyclovir: 500 mg orally twice a day for 3 to 5 days Valacyclovir: 1.0 g orally once a day for 5 days Suppressive therapies (frequent recurrences are reduced by 70% 80% with these treatments) Acyclovir: 400 mg orally, twice a day Famciclovir: 250 mg orally, twice a day Valacyclovir: 500 mg orally, once a day Valacyclovir: 1.0 g orally, once a day [5] Genital herpes in pregnancy The safety of systemic treatment with these antiviral agents in pregnant women has not been established. Women with recurrent genital herpetic lesions should deliver by cesarean section to prevent neonatal herpes infection [5]. Endometritis and salpingitis The term pelvic inflammatory disease (PID) encompasses clinically suspected endometritis or salpingitis or both that has not been confirmed pathologically or laparoscopically. Pelvic inflammatory disease is the consequence of sexually transmitted diseases moving to the upper female genital tract. Tubo-ovarian abscess is one of the major complications of acute PID and occurs in 15% of women with PID [11,13]. Pathogenesis Pelvic inflammatory disease is a polymicrobial infection. In addition to Neisseria gonorrhoeae and Chlamydia trachomatis, a variety of gram-positive and gram-negative aerobic and anaerobic pathogens, such as aerobic streptococci, Escherichia coli, Bacteroides fragilis, Proteus sp, and Peptostreptococcus sp can be recovered from the uterus, fallopian tubes, and peritoneal cavity [13]. Most PID results from ascending intracanalicular spread of lower genital tract organisms to the upper genital area. Factors in the ascent of sexually transmitted organisms include young age, minority race, tobacco abuse, douching, frequency of intercourse, number of sexual contacts, phase of menstrual cycle, and contraceptive methods. Spread could be through direct

202 S. Nasraty / Prim Care Clin Office Pract 30 (2003) 193 203 invasion of these organisms or failure of the mechanical or immunologic barrier function of the endocervix. Onset of symptoms seems to occur most often in the proliferative phase of the menstrual cycle [14]. Infertility is the most common serious outcome of salpingitis and is usually a result of endothelial tubal damage of the salpinx. Severity of clinical findings determines whether treatment should be carried out on an outpatient or inpatient basis or whether oral or intravenous antibiotic regimens are used [15]. The result of a randomized, controlled trial conducted in a large health maintenance organization indicated that screening women by a set of risk factors reduces the incidence of PID during a 1-year period [10]. In women with acute PID, C. trachomatis can be isolated from the urogenital tract in approximately 20% of the cases. Histologic evidence of plasma cell endometritis is present in most cases of laparoscopically verified salpingitis. Endometritis is also present in 40% of women with mucopurulent cervicitis and presumably progresses to salpingitis if untreated. Subclinical, undiagnosed salpingitis seems to be more common than evidence of acute disease [11]. Cefoxitin administered as 2 g intravenously every 6 hours or cefotetan given as 2 g intravenously every 12 hours plus oral doxycycline 100 mg twice daily for 14 days is the most cost-effective regimen for treating uncomplicated PID. Outpatient regimens include an initial single intramuscular dose of a second- or third-generation cephalosporin plus 14 days of oral doxycycline at 100 mg twice daily. Ofloxacin at 400 mg orally twice daily or levofloxacin at 500 mg orally once a day with or without metronidazole also may be given for 14 days. In women with tubo-ovarian abscess, hospitalization and treatment with triple-antibiotic therapy (eg, cefoxitin, clindamycin, and doxycycline) is the treatment of choice. Patients not responding to triple therapy within 48 to 72 hours should be evaluated for surgical intervention. Ultrasonography has been shown to be an accurate, sensitive, noninvasive imaging technique for diagnosing tubo-ovarian abscess [13]. Pregnant women who have suspected PID should be hospitalized and treated with parenteral antibiotics. References [1] Sobel JD. Vaginitis. New Engl J Med 1997;337:1896 903. [2] Holzman C, Leventhal JM, Qiu H, Jones NM, Wang J, BV Study Group. Factors linked to bacterial vaginosis in nonpregnant women. Am J Public Health 2001;91:1664 70. [3] Priestley CJ, Jones BM, Dhar J, Goodwin L. What is normal vaginal flora? Genitourin Med 1997;73:23 8.

S. Nasraty / Prim Care Clin Office Pract 30 (2003) 193 203 203 [4] Rein MF. Vulvovaginitis and cervicitis. In: Mandell GL, Bennett JE, Dolin R, editors. Principles and practice of infectious diseases. 5th edition. Vol. 1. Philadelphia: Churchill Livingstone; 2000. p. 1218 35. [5] Centers for Disease Control and Prevention. Sexually transmitted diseases: treatment guidelines 2002. MMWR 2002;51(RR-6):12 57. [6] Kane KY, Pierce R. What are the most effective treatments for bacterial vaginosis in nonpregnant women? J Fam Pract 2001;50:399 400. [7] Lurie S, Woliovitch I, Glezerman M. Short anovaginal distance: a risk factor for recurrent vaginitis. Int J Gynecol Obstet 2000;71:279 80. [8] Rein MF. Trichomonas vaginalis. In: Mandell GL, Bennett JE, Dolin R, editors. Principles and practice of infectious diseases. 5th edition. Vol. 1. Philadelphia: Churchill Livingstone; 2000. p. 2894 98. [9] Hillis SD, Owens LM, Marchbanks PA, Amsterdam LF, Mac Kenzie WR. Recurrent chlamydial infections increase the risks of hospitalization for ectopic pregnancy and pelvic inflammatory disease. Am J Obstet Gynecol 1997;176(1 Pt 1):103 7. [10] Nelson HD, Helfand M. Screening for chlamydial infection. Am J Prev Med 2001; 20(3 Suppl):95 107. [11] Jones RB, Batteiger BE. Chlamydia trachomatis (trachoma, perinatal infections, lymphogranuloma venereum, and other genital infections). In: Mandell GL, Bennett JE, Dolin R, editors. Principles and practice of infectious diseases. 5th edition. Vol. 1. Philadelphia: Churchill Livingstone; 2000. p. 1990 2002. [12] US Preventive Services Task Force. Screening for chlamydial infection: recommendations and rationale. Am J Prev Med 2001;20(3 Suppl):90 4. [13] McNeeley SG, Hendrix SL, Mazzoni MM, Kmak DC, Ransom SB. Medically sound, costeffective treatment for pelvic inflammatory disease and tuboovarian abscess. Am J Obstet Gynecol 1998;178:1272 8. [14] Korn AP, Hessol NA, Padian NS, Bolan GA, Donegan E, Landers DV, et al. Risk factors for plasma cell endometritis among women with cervical Neisseria gonorrhoeae, cervical Chlamydia trachomatis, or bacterial vaginosis. Am J Obstet Gynecol 1998;178:987 90. [15] Eschenbach DA, Wolner-Hanssen P, Hawes SE, Pavletic A, Paavonen J, Holmes KK. Acute pelvic inflammatory disease: associations of clinical and laboratory findings with laparoscopic findings. Obstet Gynecol 1997;89:184 92.