Human Papillomavirus

Synonyms and related keywords: human papillomavirus, HPV, wart virus, epithelial tumors, anogenital warts, mucosal warts, nongenital cutaneous warts, epidermodysplasia verruciformis, EV, sexually transmitted disease, STD, squamous intraepithelial lesions, SIL



INTRODUCTION

Background: Papillomaviruses affect a wide variety of animals. They cause tumors that erupt from DNA mutations in humans, monkeys, deer, horses, cattle, dogs, birds, and rabbits. The Los Alamos National Laboratory in the United States maintains a database of papillomavirus genomic sequences and a phylogenic tree, both of which are available at HPV Sequence Database.

Human papillomaviruses (HPVs) produce epithelial tumors of the skin and mucous membranes. More than 100 HPV types have been detected, and the genomes of more than 80 have been completely sequenced. The current classification system, which is based on similarities in their genomic sequences, generally correlates with the 3 categories used to describe HPV clinically: anogenital and/or mucosal, nongenital cutaneous, and epidermodysplasia verruciformis (EV).

The mucosal HPV infections are classified further as latent (asymptomatic), subclinical, or clinical. Clinical lesions are grossly apparent, whereas latent infections are detected only with tests for viral DNA. Subclinical lesions are identified by application of 3-5% acetic acid and inspection under magnification. Most HPV infections are latent; clinically apparent infections usually result in warts rather than malignancies.

HPV types 6 and 11 are typically labeled as low risk because infection with these types has low oncogenic potential and usually results in the formation of condylomata and low-grade precancerous lesions. HPV types 16 and 18 have emerged as the high-risk types of HPV because they are responsible for most high-grade intraepithelial lesions that may progress to carcinomas, particularly those in the anogenital and/or mucosal category.

HPV infection alone does not cause malignant transformation of infected tissue. Cofactors, such as tobacco use, ultraviolet radiation, pregnancy, folate deficiency, and immune suppression have been implicated in this process. The table lists a variety of diseases and the associated HPV subtypes.

Diseases and Associated HPV Subtypes

Nongenital Cutaneous Disease	HPV Type
Common warts (verrucae vulgaris) Warts (Nongenital)	1, 2, 4, 26, 27, 29, 41, 57, 65
Plantar warts (myrmecias) Warts, Plantar	1, 2, 4, 63
Flat warts (verrucae plana)	3, 10, 27, 28, 38, 41, 49
Butcher's warts (common warts of people who handle meat, poultry, and fish)	1, 2, 3, 4, 7, 10, 28
Mosaic warts	2, 27, 57
Ungual squamous cell carcinoma	16
Epidermodysplasia verruciformis (benign) Epidermodysplasia Verruciformis	2, 3, 10, 12, 15, 19, 36, 46, 47, 50
Epidermodysplasia verruciformis (malignant or benign) Epidermodysplasia Verruciformis	5, 8, 9, 10, 14, 17, 20, 21, 22, 23, 24, 25, 37, 38
Nonwarty skin lesions	37, 38
Nongenital Mucosal Disease	HPV Type
Respiratory papillomatosis Recurrent Respiratory Papillomatosis	6, 11
Squamous cell carcinoma of the lung	6, 11, 16, 18
Laryngeal papilloma	6, 11, 30
Laryngeal carcinoma	16, 18
Maxillary sinus papilloma	57
Squamous cell carcinoma of the sinuses	16, 18
Conjunctival papillomas	6, 11
Conjunctival carcinoma	16
Oral focal epithelial hyperplasia (Heck disease)	13, 32
Oral carcinoma	16, 18
Oral leukoplakia	16, 18
Squamous cell carcinoma of the esophagus	16, 18
Anogenital Disease	HPV Type
Condylomata acuminata	6, 11, 30, 42, 43, 44, 45, 51, 52, 54
Bowenoid papulosis Bowenoid Papulosis	16, 18, 34, 39, 42, 45
Bowen disease	16, 18, 31, 34
Giant condylomata (Buschke-Löwenstein tumors) Giant Condylomata Acuminata of Buschke and Löwenstein	6, 11
Unspecified intraepithelial neoplasia	30, 34, 39, 40, 53, 57, 59, 61, 62, 64, 66, 67, 68, 69
Low-grade intraepithelial neoplasia	6, 11, 43
Intermediate intraepithelial neoplasia	31, 33, 35, 42, 44, 45, 51, 52
High-grade intraepithelial neoplasia	16, 18, 56, 58
Carcinoma of vulva Malignant Vulvar Lesions	6, 11, 16, 18
Carcinoma of vagina	16
Carcinoma of cervix Cervical Cancer	16, 18, 31
Carcinoma of anus	16, 31, 32, 33
Carcinoma in situ of penis (erythroplasia of Queyrat)	16
Carcinoma of penis	16, 18

Pathophysiology: Papillomaviruses are highly species specific and do not infect other species, even under laboratory conditions. Humans are the only known reservoir for HPV. Papillomaviruses are nonenveloped viruses of icosahedral symmetry with 72 capsomeres that surround a genome containing double-stranded circular DNA with approximately 8000 base pairs.

Papillomaviruses are thought to have 2 modes of replication. One is stable replication of the episomal genome in basal cells; the other is runaway, or vegetative, replication in more differentiated cells to generate progeny virus. Although all cells of a lesion contain the viral genome, the expression of viral genes is tightly linked to the state of cellular differentiation. Most viral genes are not activated until the infected keratinocyte leaves the basal layer. Production of virus particles can occur only in highly differentiated keratinocytes; therefore, virus production only occurs at the epithelial surface where the cells are ultimately sloughed into the environment.

HPV lesions are thought to arise from the proliferation of infected basal keratinocytes. Infection typically occurs when basal cells in the host are exposed to infectious virus through a disturbed epithelial barrier as would occur during sexual intercourse or after minor skin abrasions. HPV infections have not been shown to be cytolytic, rather viral particles are released as a result of degeneration of desquamating cells. The HPV virus can survive for many months and at low temperatures without a host; therefore, an individual with plantar warts can spread the virus by walking barefoot.

Virus multiplication is confined to the nucleus. Consequently, infected cells exhibit a high degree of nuclear atypia. Koilocytosis (from the Greek koilos, meaning empty) describes a combination of perinuclear clearing (halo) with a pyknotic or shrunken (rasinoid) nucleus and is a characteristic feature of productive papillomavirus infection.

The HPV genome exists as a circular episomal DNA separate from the host cell nucleus in benign or low-risk HPV lesions, such as those typically associated with HPV types 6 and 11. The genomes of high-risk HPV types 16 and 18 are typically integrated into the host cell DNA in malignant lesions. Integration of the viral genome into the host cell genome is considered a hallmark of malignant transformation. HPV proteins E6 and E7 of high-risk serotypes have been shown to inactivate the host's tumor suppressor proteins p53 and Rb, thereby resulting in unregulated host cell proliferation and malignant transformation.

Frequency:

• In the US: The number of patients identified with HPV disease has increased markedly during the past 20 years because of heightened awareness of the various manifestations of HPV disease and because of increased use of HPV DNA testing.

  Patients receiving immunosuppressive drugs and patients with defects in cell-mediated immunity, including those infected with the human immunodeficiency virus (HIV), are especially susceptible to developing HPV infections.

  In the United States, 2.5 million women are estimated to have an annual cytological diagnosis of a low-grade cervical cancer precursor.

  The incidence of Cervical Cancer has decreased dramatically during the last century because of implementation of the Papanicolaou test (Pap Test, or Pap smear) beginning in the 1930s and 1940s. However, from 1990-2001 the annual number of estimated new invasive cervical cancers has remained relatively constant, ie, 13,500 and 12,900, respectively.

  Anogenital warts, or condylomata acuminata, are the most commonly diagnosed viral sexually transmitted disease (STD) in the United States and the United Kingdom. The annual incidence is estimated between 500,000 and 1 million cases. From 1966-1986, the incidence of genital warts has increased 5-fold.

  Approximately 7-10% of the population has nongenital cutaneous warts.

• Internationally: The worldwide prevalence of HPV in cervical carcinoma is 95-99.7% and in anal cancer is 88%.

  In many lesser-developed countries, cervical cancer is the most common cancer among women because of the lack of effective screening programs that monitor cervical cytology by Pap smear.

  In many developing nations, cervical cancer is the leading cause of cancer mortality among women. Worldwide, it is the second most common cause of cancer mortality among women.

Mortality/Morbidity:

• Anogenital/mucosal disease: A direct correlation exists between anogenital HPV infection and measures of sexual activity, such as the age of first intercourse and the lifetime number of sexual partners. Women with a history of a cervical high-grade squamous intraepithelial lesion (HGSIL) or invasive squamous cell carcinoma (SCC) of the cervix are at increased risk for subsequent development of invasive cancer in other tissues of the anogenital/mucosal category, particularly vaginal and anal carcinoma. In these patients, the relative risk of vaginal carcinoma is 5.6, and the risk of anal carcinoma is 4. Anal cancer has been strongly associated with male homosexuality and specific male practices, such as engaging in receptive anal intercourse. Relative risk is 33. However, the overall disease prevalence is higher in women than in men, with a female-to-male ratio of 1.5:1.

• Nongenital cutaneous warts: Cutaneous lesions typically produce benign self-limited warts (see Warts [Nongenital]).

• EV: Patients who are immunosuppressed, particularly those with cutaneous malignant lesions, have a much higher incidence of EV-HPV infection than the general population. These lesions can undergo malignant transformation. Ten percent of patients with EV originate from consanguineous marriages, suggesting an autosomal recessive mode of inheritance (see Epidermodysplasia Verruciformis).

Race:

• From 1987-1991, the age-adjusted Cervical Cancer death rate reported by the US National Cancer Institute was higher among black women compared to white women, with a ratio of 6:1.

• Nongenital cutaneous warts are more common in whites than in people of African descent.

Sex:

• The overall prevalence of HPV in women is 22-35%.

• In men, the prevalence is 2-35% depending on the sexual practices of the population being studied.

Age:

• Anogenital mucosal HPV infections are highest among college-aged women and men.

• Nongenital cutaneous warts are more common among teenagers and adults who work as meat, poultry, and fish handlers. The incidence approaches 10% in child and young adult populations. However, nongenital cutaneous warts rarely occur in people younger than 5 years and usually regress within 2 years.

• EV develops at an average age of onset of 6 years, and, beginning in the fourth decade of life, the lesions can undergo malignant transformation into invasive SCC.

CLINICAL

History:

• Anogenital warts

• Condylomata acuminata are exophytic cauliflowerlike lesions that are usually found near moist surfaces. They may be observed in the perianal area, vaginal introitus, vagina, labia, and vulva. Genital warts may also be found on dry surfaces, such as the shaft of the penis.

• Genital warts include smooth papular warts and keratotic warts, the latter of which resemble nongenital cutaneous warts because of their thickened bumpy surface.

• Genital flat warts are subclinical lesions that typically appear on the cervix. Colposcopic examination with 3% acetic acid solution is required for identification.

• Cervical disease

• Most cervical infections are either latent or subclinical and, as such, are asymptomatic. These infections are detected on Pap smear and are reported as either a low-grade squamous intraepithelial lesion (LGSIL) or a high-grade squamous intraepithelial lesion (HGSIL). Further examination with 3-5% acetic acid and colposcopy shows characteristic acetowhite changes and abnormal blood vessels indicative of HPV-triggered dysplasia.

• Patients who have neglected to obtain annual Pap testing for several years or more and who have an HGSIL that has progressed to invasive cancer of the cervix may report vaginal bleeding between periods or after sexual intercourse, dyspareunia, and fullness in the pelvis.

• Anal cancer

• The most common presenting symptoms of SCC of the anus are rectal bleeding and sensation of a mass. This may be attributed mistakenly to hemorrhoids.

• Fifty percent of men who are homosexual and have SCC of the anus have a history of anorectal warts; however, only 20% of women with SCC and men who are not homosexual have this history.

• Nonanogenital mucosal disease

• HPV types 6 and 11 have been isolated on nonanogenital mucosal surfaces. Warts have been discovered in the nares, mouth, larynx, and conjunctiva.

• HPV types 6 and 11 are associated with respiratory papillomas that are probably the result of intrapartum transmission when the infant passes through the birth canal of a mother who is infected with HPV. However, isolated case reports exist of respiratory papillomatosis after cesarean delivery. Patients with laryngeal papillomas present at an average age of 3 years, most frequently with hoarseness.

• Nongenital cutaneous HPV

• Cutaneous lesions typically produce benign self-limited warts.

• Deep plantar warts occur most commonly as solitary lesions that may become black and painful prior to spontaneous regression. They may contain small black “seeds,” which are thrombosed capillaries.

• Common warts can occur on any skin surface but are usually found on the hands and fingers. They appear as skin-colored, exophytic, rough papules and nodules that have minimal scaling. Autoinoculation from a wart on one finger may cause the occurrence of warts on an adjacent finger or other skin surface, so-called kissing warts.

• Warts that occur in people who handle meat and fish often have large cauliflowerlike plaques.
• Flat warts most often occur in groups of small plaques less than 5 mm in diameter on the face and hands. Regression usually occurs spontaneously after several years, and pruritus or erythema occur several weeks prior to their disappearance.

• Epidermodysplasia verruciformis

• The malignant conversion of skin lesions usually begins in the fourth and fifth decades of life. Premalignant lesions usually first arise on the forehead and other sun-exposed areas. The tumors are either benign papillomas and seborrheic keratoses or premalignant actinic keratoses and SCC.
• EV tumors are locally destructive. They develop slowly and have weak metastatic potential if no cocarcinogens, such as x-ray or ultraviolet B irradiation, are applied. Polymorphic, plane wart–like, and red-to-brownish plaques can be distributed widely over the skin. The lymph nodes and oral mucosa are not involved.

Physical: The findings on physical examination depend on the tissues involved. They include a variety of cutaneous lesions with characteristic appearances noted above. Images 1-4 demonstrate extensive anogenital condyloma acuminata.

Causes:

• Types of HPV demonstrate a high degree of site specificity, with some HPV types only found on certain parts of the skin or mucous membranes.

• HPV infection alone does not cause malignant transformation of infected tissue. Cofactors, such as tobacco use, ultraviolet radiation, pregnancy, folate deficiency, and immune suppression, have been implicated in this process. Patients receiving immunosuppressive drugs and patients with defects in cell-mediated immunity, including those infected with HIV are especially susceptible to developing HPV infections.

• A direct correlation exists between anogenital HPV infection and measures of sexual activity, such as the age of first intercourse and the lifetime number of sexual partners.

DIFFERENTIALS

Benign Cervical Lesions
Benign Vulvar Lesions
Carbon Dioxide Laser Surgery of the Lower Genital Tract
Cervical Cancer
Conization of Cervix
Gynecologic Cryosurgery
Hemorrhoids
Hidradenitis Suppurativa
Malignant Vulvar Lesions
Molluscum Contagiosum
Penile Cancer
Recurrent Respiratory Papillomatosis
Surgical Treatment of Vaginal Cancer
Surgical Treatment of Vulvar Cancer
Urethral Warts

Other Problems to be Considered:

Actinic keratoses
Carbon dioxide laser surgery for intraepithelial cervical neoplasms
Cervical polyp
Condyloma lata
Dermatitis papillaris
Nevi
Oropharyngeal SCC
Pityriasis versicolor
Sinonasal Papillomas, Treatment
Warts (Nongenital)
Pap Test
Recurrent Respiratory Papillomatosis
Squamous Cell Carcinoma
Warts, Plantar
Bowenoid Papulosis
Warts
Epidermodysplasia Verruciformis
Squamous Cell Carcinoma, Eyelid
Warts (Genital)
Giant Condylomata Acuminata of Buschke and Löwenstein
Acanthosis Nigricans
Acrochordon
Corns and Calluses
Keloid and Hypertrophic Scar
Keratoacanthoma
Lichen Planus
Psoriasis (Plaque)
Seborrheic Keratosis
Malignant Tumors of the Mobile Tongue

WORKUP

Lab Studies:

• Cytologic testing

• Cervical cytologic testing using the Pap test is the standard screening procedure for cervical neoplasia. It should be performed annually in all women beginning 3 years after they become sexually active or when they have reached age 21 years if they have remained abstinent. Once a woman has had findings within the reference range on 3 or more consecutive annual Pap smears, the Pap smear may be performed less frequently if the patient is at low risk for developing cervical dysplasia.

• Pap smears should contain samples of cells from the ectocervix, transformation zone, and endocervical canal. Perform the test when the patient is not menstruating so that the cytologic specimen is not occluded with blood. Furthermore, if the patient has a cervicovaginal infection with a mucopurulent vaginal discharge, consider performing the test after the bacterial infection has resolved. If the test must be performed, the discharge should be gently cleared with a saline-moistened cotton swab.

• This test may be modified as required to sample tissues of the vagina, vulva, or perianal region that are suspicious for intraepithelial neoplasia. Although not an established routine, consider performing annual anal Pap smears on men who have high risk and who participate in receptive anal intercourse. See Cervical Cancer for guidelines on how often to perform the Pap smear when abnormalities result.

• Liquid-based Pap smears improve the diagnostic sensitivity of cervical cytology screening. They have the additional benefit of enabling easy testing for HPV. Thin Prep and SurePath are the 2 methods currently approved by the US Food and Drug Administration (FDA).

• HPV DNA typing

• The 2 common methods for HPV DNA testing include the Hybrid Capture II (HC II) and the polymerase chain reaction (PCR) enzyme immunosorbent assay. Both of these methods have similarly high sensitivities and are suitable tools for detection of HPV and posttreatment follow-up of cervical intraepithelial neoplasia (CIN).

• HPV DNA testing is the preferred approach in the treatment of women whose Pap test results show atypical squamous cells of undetermined significance (ASC-US) whenever liquid-based cytology is used or co-collection is available. HPV DNA testing is also useful in the management of CIN in certain situations. Detailed consensus guidelines for management of abnormal Pap test results and management of CIN are available at American Society for Colposcopic and Cervical Pathology.

Procedures:

• Tissue biopsy

• Tissue biopsy can be used to confirm HPV infection if the diagnosis is uncertain, particularly if warts are abnormally pigmented, ulcerated, or indurated.

• Obtain a biopsy of a warty lesion if the patient is immunocompromised, if the lesions worsen during treatment, or if they do not respond to standard therapy. In addition, biopsy is recommended to clarify the diagnosis in older patients who are at risk for genital carcinoma.

Histologic Findings: Virus multiplication is confined to the host cell nucleus. Consequently, infected cells exhibit a high degree of nuclear atypia. Koilocytosis describes a combination of perinuclear clearing with a pyknotic or shrunken nucleus and is a characteristic feature of productive papillomavirus infection. Other cytologic markers of HPV infection include acanthosis, dyskeratosis, and multinucleation.


TREATMENT

Medical Care: Eradication or reduction of symptoms is the primary goal of treating warts, but elimination of dysplastic lesions is the goal in treating squamous intraepithelial lesions (SILs). Treatment is not recommended for subclinical anogenital and/or mucosal HPV infection in the absence of coexistent dysplasia. No evidence demonstrates that treatment eliminates HPV infection or that it decreases infectivity. In fact, warts may recur after treatment because of activation of latent virus present in healthy skin adjacent to the lesion.

Superiority of any single treatment modality has not been demonstrated, nor is one modality ideal for all types of warts. Factors that influence treatment of HPV disease include the size, morphology, number, and anatomic site of lesions, as well as cost, adverse effects, patient preference, and provider experience.

Most patients with warts require multiple treatments over a course of several weeks or months. If substantial improvements have not occurred after 3 physician-administered treatments or if complete clearance has not occurred after 6 treatments, a different treatment modality should be used.

Treatment

All medicines used to treat HPV disease are applied topically on cutaneous surfaces. Local skin reactions and pain are common adverse effects. Do not apply any of these medications to mucosal surfaces and do not use them to treat dysplastic lesions, SCC, verrucous carcinomas, or Bowenoid Papulosis.

Two broad categories of medications are effective in treating HPV disease. The first category, the immune response modifiers (ie, imiquimod, interferon alfa), is primarily used in treatment of external anogenital warts or condylomata acuminata. The second category consists of the cytotoxic agents, which include the antiproliferative drugs podofilox, podophyllin, and 5-fluorouracil, as well as the chemodestructive or keratolytic agents salicylic acid, trichloroacetic acid (TCA), and bichloroacetic acid (BCA).

None of these medicines has been shown to be uniformly effective or directly antiviral. The keratolytics are the only agents that are recommended for treatment of nongenital cutaneous warts.

• Imiquimod

• This immune response modifier has no direct antiviral activity; however, it is a powerful cytokine inducer, which stimulates production of interferon alfa, tumor necrosis factor, and interleukin (IL)-1, IL-6, and IL-8.
• This patient-applied treatment is used for the treatment of external anogenital warts and condyloma acuminatum. It is applied 3 times per week, with application approximating an every-other-day routine (eg, Monday, Wednesday, Friday). Remove the cream by washing with mild soap and water 6-10 hours after application.
• Treatment continues until the warts have completely cleared, up to a maximum of 16 weeks.
• Local skin reactions are common, especially following contact with mucosal surfaces.

• Interferon alfa

• This naturally occurring cytokine is produced by recombinant DNA technology or by collection from pooled human leukocytes. It has potent immunomodulatory, as well as direct antiviral, effects.
• This physician-applied medicine is used for intralesional treatment of external anogenital warts and condyloma acuminatum. It is injected into the base of each wart, preferably using a 30-gauge needle. For large warts, it may be injected at several points around the periphery of the wart, using a total dose of 250,000 IU per wart. Direct the needle at the center of the base of the wart and at an angle almost parallel to the plane of the skin (approximating that in the commonly used purified protein derivative [PPD] test).
• The maximum response usually occurs 4-8 weeks after initiation of the first treatment course. If results at 12-16 weeks following the initial treatment course with interferon alfa-2b are not satisfactory, a second course of treatment using the same dosage schedule may be instituted, providing that clinical symptoms and signs or changes in laboratory parameters (eg, liver function tests, WBC count, platelet count) do not preclude such a course of action.
• Patients with 6-10 condylomata may receive a second (sequential) course of treatment using the same dosage schedule to treat up to 5 additional condylomata per course of treatment. Patients with more than 10 condylomata may receive additional sequences depending on how many condylomata are present.

• Podofilox
  • This antimitotic drug is either chemically synthesized or purified from naturally occurring podophyllin resin. Application stimulates visible necrosis of wart tissue.
  • This patient-applied medicine is used in the treatment of external genital warts or condyloma acuminatum. It is applied twice a day for 3 days, followed by 4 days of no therapy. This cycle can be repeated for a maximum of 4 cycles.
  • To ensure that the patient is fully aware of the correct method of therapy and to identify which specific warts should be treated, the prescriber should demonstrate the technique for initial application of the medication.
  • No more than 0.5 g of gel per day should be used. Limit the total wart tissue treated to 10 cm² or less.

• Podophyllin
  • This resin derived from the Mayapple (Podophyllum peltatum Linné) contains the active agent podophyllotoxin, which is a cytotoxic agent that arrests mitosis in metaphase.
  • Podophyllin is a physician-applied medicine used in the treatment of external genital warts and condyloma acuminatum. It can be applied weekly for up to 6 weeks.
  • Prior to application, thoroughly cleanse the affected area. Avoid contact with healthy tissue. Apply the medicine sparingly and allow to dry thoroughly.
  • Initial application should be for 30-40 minutes. Subsequent applications can be for 1-4 hours. Remove dried podophyllin with alcohol or with soap and water. Do not treat large areas or numerous warts at once.
• 5-Fluorouracil
  • This antimetabolite interferes with the synthesis of DNA and RNA. This action creates a thymine deficiency, resulting in unbalanced growth and death of a cell.
  • This patient-applied treatment is not formally indicated for treatment of HPV disease; however, the 5% cream formulation can be helpful in the treatment of some genital warts. It is applied 1-3 times per week for several weeks as needed.
  • Prior to application, thoroughly cleanse the affected area. Avoid contact with healthy tissue. Apply the medicine sparingly and allow to dry thoroughly. Remove dried cream 3-10 hours after application.
• Keratolytics
  • TCA and BCA are extremely powerful keratolytic agents that rapidly penetrate and chemically cauterize skin, keratin, and other tissues. The cauterizing effect is comparable to cryotherapy or electrodesiccation. These physician-applied agents can be used on all types of cutaneous warts.
  • An 80-90% solution is applied directly on a weekly basis. As the acid dries, a white frosting develops and should be powdered with sodium bicarbonate to remove any unreacted acid.
  • Salicylic acid is a milder keratolytic that is typically purchased in nonprescription formulations. This patient-applied medicine is used primarily to treat nongenital cutaneous warts.

Surgical Care: Various surgical techniques are available for the treatment of HPV disease. With the exception of cryosurgery, these modalities usually have the common advantage of complete treatment following one application. However, surgical modalities typically require local anesthesia and more time and equipment to implement. Consequently, they are often used when a large number of warts is present or a large area is affected or on patients with refractory disease. Recurrence of HPV disease is less common following surgical treatment as opposed to medical therapy.

Primary surgical therapy can often be accomplished in the office and includes cryosurgery; electrosurgery with either electrodesiccation or loop electrosurgical excision procedure (LEEP); or simple surgical excision with a scalpel, scissors, or curette.

Alternative surgical procedures requiring more advanced equipment and training include carbon dioxide laser ablation, Cavitron Ultrasonic Surgical Aspiration (CUSA), or Mohs surgery.

• Cryosurgery (see Gynecologic Cryosurgery for further discussion)

• This physically ablative method is a rapid and effective means of treating simple HPV disease. It works by freezing the intracellular water, resulting in cellular destruction.
• Although it is somewhat painful, local anesthesia is not usually used. After 2-4 treatments in a 6- to 12-week period, 75-80% of patients experience a complete clearing of warts.
• This method is effective for most simple cutaneous warts and for low-grade cervical intraepithelial neoplasia (CIN I). It is not recommended for use in the vagina because the depth of ablation cannot be controlled and damage to adjacent structures, such as the bladder and rectum, is possible.
• Liquid nitrogen is applied to the wart using a cotton-tipped applicator, a cryoprobe, or a fine spray. Gases, such as nitrous oxide and carbon dioxide, can also be used.
• The freeze-thaw-freeze method is considered more effective than a single freeze. Application is continued until up to a 5-mm margin of surrounding skin or mucosa is frozen. After the skin turns white, freezing is continued for 30 seconds and then the skin is allowed to thaw. If the patient can tolerate the pain, a second cycle is applied.
• Within 24 hours after treatment, a bulla forms over the treated area. An additional course of treatment can be applied in 1-2 weeks as needed. This treatment modality is safe for use in women who are pregnant because it is not systemically absorbed.

• Electrosurgery

• These modalities use high-frequency current to cut and coagulate warts. Electrodesiccation using a bipolar needle can be used to coagulate wart tissue deeply. This is most effective with external genital warts.
• LEEP uses a bipolar loop to vaporize and fulgurate affected tissue. It is primarily used to treat cervical SILs; however, it may also be used to remove large external genital warts.
• Electrosurgical methods usually require only local anesthesia and may be employed in an outpatient setting if the appropriate equipment is available.
• HPV DNA has been found in smoke plumes; therefore, procedures to evacuate the smoke and prevent inhalation must be used.

• Surgical removal

• Simple surgical excision with a scalpel, scissors, or curette can be performed under local anesthesia to remove warts and treat SILs of the genital tract.
• Mohs surgery can be performed by specially trained dermatologists to excise tissue in areas where maximum conservation is required. This method uses dermatopathology in conjunction with conservative excision of malignant lesions. It may be of particular assistance in managing verrucous carcinomas.

• Laser surgery (see Complications of Dermatologic Laser Surgery for further discussion)

• Carbon dioxide laser vaporization is an alternative surgical procedure that is typically used for treatment of refractory HPV disease or extensive warts of the anogenital/mucosal category. This precisely controlled modality conserves normal adjacent tissue. It is particularly useful in treatment of periurethral and vaginal warts and vaginal SILs.
• HPV DNA has been found in laser smoke plumes; therefore, procedures to evacuate the smoke and prevent inhalation must be used.

• Cavitron Ultrasonic Surgical Aspirator

• This device vibrates at a frequency of 23 kHz, which is an order of magnitude lower than the frequency of a diagnostic ultrasound. It destroys tissue through heat and cavitation.
• CUSA has been used extensively for cytoreduction of intra-abdominal tumors because of the ability to remove epithelium without damage to underlying tissue. Consequently, it has been employed as an alternative therapy for extensive anogenital warts.

Consultations:

• Consult a gynecologic oncologist for assistance in management of genital tract SILs and carcinomas, as well as exophytic cervical warts and giant condylomata.

• Consult a urologist or a urogynecologist for assistance with surgical management of urethral warts, penile condylomata, SILs, or carcinomas.

• Consult a colorectal surgeon for assistance with the surgical management of perianal condylomata or anal SILs or carcinomas.

• Consult an otolaryngologist for assistance with management of oropharyngeal papillomas or SCC.

• Consult a dermatologist in the following cases:
  • Consult a dermatologist for assistance with management of EV.
  • Bleeding warts, moles, birthmarks, or unusual warts with hair growing from them can be confused with HPV disease. Refer these types of lesions to a dermatologist for diagnostic clarification.
  • Dermatologists who specialize in Mohs surgery, which uses dermatopathology in conjunction with the conservative excision of malignant lesions, may be of particular assistance in managing verrucous carcinomas.

• Consult an infectious disease specialist for assistance in management of HPV disease in patients who are immunocompromised.

Diet: Folate deficiency is the only dietary factor that has been shown to play a role in early cervical carcinogenesis. Folate deficiency apparently facilitates incorporation of HPV DNA at a fragile chromosomal site, thereby establishing a basis for malignant transformation.

Activity: Certain activities are associated with an increased risk of HPV malignant transformation, particularly in the anogenital/mucosal category.

• Sexual activity

• A direct correlation exists between anogenital HPV infection and measures of sexual activity, such as the age of first intercourse and the lifetime number of sexual partners.
• Women with a history of cervical HGSIL or invasive SCC of the cervix are at increased risk for subsequent development of invasive cancer in other tissues of the anogenital/mucosal category, particularly vaginal and anal carcinoma, with relative risks of 5.6 and 4 respectively.
• Anal cancer has been strongly associated with male homosexuality and with specific male practices, such as engaging in receptive anal intercourse; relative risk is 33. However, the overall disease prevalence is higher in women than in men, with a female-to-male ratio of 1.5:1.

• Tobacco smoking

• Women who smoke tobacco have an increased risk of developing cervical neoplasia.
• Measurable amounts of a potent carcinogen, as well as several compounds from cigarette smoke, have been identified in the cervical mucus of females who smoke. These agents are likely to play a role in the increased prevalence of HPV malignant transformation of patients who smoke tobacco.

• Oral contraceptive use
  • Women who use oral contraceptives for longer than 5 years have an increased relative risk of developing cervical carcinoma.
  • This risk declines after stopping oral contraceptives, and no risk is demonstrated in users of less than 5 years duration.

• Chewing Indian betel quid
  • A high incidence of oral cancer associated with HPV infection has been demonstrated in India among patients who chew betel quid.
  • This stimulant is made from the leaves of the betel plant and is used in a manner similar to chewing tobacco.
• Ultraviolet and x-ray irradiation: EV is particularly susceptible to UV and x-ray irradiation; therefore, patients with EV should avoid activities that unnecessarily expose them to these forms of radiation.

MEDICATION

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Drug Category: Immune response modifiers -- These agents have immunomodulatory effects and are used for treatment of external anogenital warts or condyloma acuminatum.

Drug Name	Imiquimod (Aldara) -- Induces secretion of interferon alfa and other cytokines. Mechanisms of action are unknown.
Adult Dose	Apply 3 times per wk, leave on skin for 6-10 h, remove by washing; treatment not to exceed 16 wk
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Not recommended for treatment of rectal, cervical, intravaginal, urethral, and intra-anal HPV infection; following surgery or drug treatment, do not use until genital/perianal tissue is healed; avoid sexual (ie, genital, anal, oral) and eye contact while the cream is on the skin; may weaken vaginal diaphragms and condoms, concurrent use is not recommended

Drug Name	Interferon alfa-n3 (Alferon N) and interferon alfa-2b (Intron A) -- Protein product manufactured from either a single-species recombinant DNA process or from pooled units of donated human leukocytes that have been induced by incomplete infection with a murine virus. Mechanisms by which it exerts antiviral activity are not understood clearly. However, modulation of the host immune response may play an important role. Indicated for intralesional treatment of refractory or recurring external condyloma acuminatum. Particularly useful for patients who have not responded satisfactorily to other treatment modalities (eg, podophyllin resin, surgery, laser, cryotherapy).
Adult Dose	Interferon alfa-n3: 0.05 mL (250,000 IU) per wart 2 times/wk for up to 8 wk; maximum recommended dose per treatment session is 0.5 mL (2.5 million IU) Interferon alfa-2b: 1 million IU injected into each lesion 3 times/wk on alternate d for 3 wk; maximum recommended dose per treatment session is 5 million IU
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity to mouse IgG, egg protein, or neomycin
Interactions	Potential risk of renal failure when administered concurrently with IL-2; theophylline may increase toxicity by reducing clearance; cimetidine may increase antitumor effects; zidovudine and vinblastine may increase toxicity
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Depression and suicidal ideation may be adverse effects of treatment; infrequently, severe or fatal GI hemorrhage has been reported; prior to initiation of therapy, perform tests to quantitate peripheral blood hemoglobin, platelets, granulocytes, hairy cells, and bone marrow hairy cells; monitor periodically (eg, monthly) during treatment to determine response to treatment; if no response within 6 mo, discontinue treatment; if a response occurs, continue treatment until no further improvement is observed and laboratory parameters have been stable for about 3 mo; not known whether continued treatment after that time is beneficial; because the manufacturing process, strength, and type of interferon (eg, natural human leukocyte interferon versus single-species recombinant interferon) may vary for different interferon formulations, changing brands may require a change in dosage (do not change interferon product without considering these factors); fever and other flulike symptoms associated with this product; caution in debilitating medical conditions (eg, unstable angina, uncontrolled congestive heart failure, chronic obstructive pulmonary disease, diabetes mellitus with ketoacidosis, coagulation disorders, severe myelosuppression, seizure disorders)

Drug Category: Antimitotic agents -- Interfere with mitosis. Many are chemotherapeutic agents. The drugs listed below are used specifically for treatment of external anogenital warts or condyloma acuminatum.

Drug Name	Podofilox (Condylox) -- Topical antimitotic that can be synthesized chemically or purified from plant families Coniferae and Berberidaceae (eg, species of Juniperus and Podophyllum). Treatment results in necrosis of visible wart tissue. Exact mechanism of action unknown.
Adult Dose	0.5% gel or solution applied to anogenital warts bid for 3 consecutive d, then discontinue; repeat cycle until no visible wart tissue or maximum of 4 cycles
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Avoid contact with eyes; if eye contact occurs, immediately flush eye with copious quantities of water and seek medical advice; not for use on mucous membranes of genital area, including urethra, rectum, and vagina; not to exceed frequency of application or duration of usage

Drug Name	Podophyllin (Podocon-25, Podofin) -- Derived from Mayapple (Podophyllum peltatum Linné) and contains the active agent podophyllotoxin, which is a cytotoxic agent that arrests mitosis in metaphase. American podophyllum contains one fourth the amount of Indian source.
Adult Dose	25% podophyllin in benzoin tincture applied only by a physician and never dispensed to a patient; reapply each wk for up to 6 wk
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; diabetes; impaired peripheral circulation
Interactions	None reported
Pregnancy	X - Contraindicated in pregnancy
Precautions	Powerful caustic and severe irritant; do not use if surrounding tissue is swollen or irritated; do not apply 25% solution near mucous membranes; do not use large amounts; avoid contact with cornea (if contact occurs, flush with copious amounts of warm water); avoid use on mucous membranes, eyes, bleeding warts, moles, birthmarks, or unusual warts with hair

Drug Category: Antimetabolites -- Interfere with nucleic acid synthesis. Chemotherapeutic agents not formally approved for use against warts. Some studies have demonstrated a benefit against external anogenital warts or condyloma acuminatum.

Drug Name	Fluorouracil (Efudex) -- Interferes with synthesis of DNA and RNA, which creates thymine deficiency resulting in unbalanced growth and cell death.
Adult Dose	5% strength applied as thin layer 1-3 times/wk; therapy may be required for up to 10-12 wk
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	X - Contraindicated in pregnancy
Precautions	Incidence of inflammatory reactions may occur with occlusive dressings; reports of vaginal ulcerations and vaginal adenosis with clear cell carcinoma following treatment; not recommended for treatment of vaginal condyloma; increased absorption through ulcerated or inflamed skin; minimize ultraviolet irradiation exposure during and immediately following treatment (reaction intensity may increase); only the 5% strength is recommended

Drug Category: Keratolytics -- Used to aid in removal of keratin in hyperkeratotic skin disorders, including corns, ichthyoses, common warts, flat warts, and other benign verrucae.

Drug Name	Trichloroacetic acid and bichloracetic acid (TCA & BCA) -- Extremely powerful keratolytic agents that rapidly penetrate and chemically cauterize skin, keratin, and other tissues. Can be used to treat nongenital cutaneous warts, as well as external anogenital warts or condyloma acuminatum.
Adult Dose	80-90% solution applied directly by physician per wk
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	External use only; restrict use to treatment areas only; avoid contact with eyes (if eye contact occurs, immediately flush with copious quantities of water and seek medical advice); not for use on premalignant or malignant lesions

Drug Name	Salicylic acid (Compound W) -- By dissolving the intercellular cement substance, salicylic acid produces desquamation of the horny layer of skin, while not affecting structure of viable epidermis. For removal of nongenital cutaneous warts, particularly common or plantar warts. Prior to application, wash affected area. May soak wart in warm water for 5 min. Dry area thoroughly.
Adult Dose	17% by weight solution or gel: Apply to wart and let dry bid/tid prn until wart removed for up to 12 wk 40% by weight solution adsorbed to medicated discs: Apply over wart and cover for 48 h, replace prn until wart removed for up to 12 wk
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Use of this medication with other topical drying agents (eg, tretinoin, sulfur, resorcinol, benzoyl peroxide) or topical medicated or alcohol-containing preparations (eg, aftershave, toiletries, skin cleansers, cosmetics) may have a cumulative drying or irritating effect, leading to desquamation and skin erosion
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Avoid contact with mucous membranes, normal skin surrounding warts, and eyes; immediately flush with water for 15 min if contact with eyes or mucous membranes occurs; avoid inhaling vapors; prolonged use in infants, people with diabetes, and patients with impaired circulation is contraindicated; not for use on moles, birthmarks, warts with hair growing from them, genital or facial warts, warts on mucous membranes, irritated skin, or any area that is infected or reddened

Drug Category: Miscellaneous topical ointment -- Kunecatechins is another topical product that has gain FDA approval for genital warts.

Drug Name	Kunecatechins (Veregen) -- Botanical drug product for topical use that consists of extract from green tea leaves. Mode of action unknown but does elicit antioxidant activity in vitro. Indicated for topical treatment of external genital and perianal warts (condylomata acuminatum) in immunocompetent patients.
Adult Dose	Apply topically tid; use approximately a 0.5-cm strand of ointment topically for each external genital or perianal wart
Pediatric Dose	less than 18 years: Not established
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Not evaluated for urethral, intravaginal, cervical, rectal, or intra-anal HPV disease and should not be used to treat these conditions; avoid application to open wounds, eyes, and nose; wash hands before and after application; avoid sexual contact while ointment is on skin; may cause application-site reactions, phimosis, inguinal lymphadenitis, urethral meatal stenosis, dysuria, genital herpes simplex, vulvitis, hypersensitivity, pruritus, pyodermitis, skin ulcer, erosions in the urethral meatus, and superinfection of warts and ulcers

Drug Category: Vaccines -- A human papillomavirus vaccine is now available for the prevention of HPV-associated dysplasias and neoplasia, including cervical cancer, genital warts (condyloma acuminata), and precancerous genital lesions. Girls and young women aged 9-26 years should receive the complete immunization series.

Drug Name	Papillomavirus vaccine (Gardasil) -- Quadrivalent HPV recombinant vaccine. First vaccine indicated to prevent cervical cancer, genital warts (condyloma acuminata), and precancerous genital lesions (eg, cervical adenocarcinoma in situ; cervical intraepithelial neoplasia grades 1, 2, and 3; vulvar intraepithelial neoplasia grades 2 and 3; vaginal intraepithelial neoplasia grades 2 and 3) due to HPV types 6, 11, 16, and 18. Vaccine efficacy mediated by humoral immune responses following immunization series.
Adult Dose	less than 26 years: 0.5 mL IM administered as 3 separate doses; administer second and third doses 2 and 6 mo after first dose, respectively >26 years: Not established
Pediatric Dose	less than 9 years: Not established >9 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Immunosuppressive therapies (eg, irradiation, antineoplastic agents, corticosteroids) may decrease immune response to vaccine
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Shake well before administering; administer in deltoid region of upper arm or in higher anterolateral thigh; individuals with impaired immune responsiveness (eg, HIV infection, neoplastic disease, currently taking immunosuppressive drugs) may not elicit antibody response; because of IM administration, do not administer to individuals with bleeding disorders (eg, thrombocytopenia, coagulation disorders, anticoagulant therapy); common adverse effects include pain, swelling, erythema, and/or pruritus at injection site and fever

FOLLOW-UP

Deterrence/Prevention:

• The FDA has recently approved a vaccine for HPV.

Complications:

• Complications of wart treatment are rare. Complications are generally confined to the treatment site and include scarring and, in the case of genital warts, vulvodynia or hyperesthesia.

• Surgical complications of treating SILs are discussed in the articles involving those diseases. See the following articles for discussion of complications:

• Benign Vulvar Lesions

• Carbon Dioxide Laser Surgery of the Lower Genital Tract
• Complications of Dermatologic Laser Surgery

• Cervical Cancer

• Conization of Cervix

• Gynecologic Cryosurgery

• Urethral Warts

• Surgical Treatment of Vulvar Cancer

• Malignant Vulvar Lesions
• Penile Cancer
• Surgical Treatment of Vaginal Cancer

Prognosis:

• Approximately two thirds of patients with nongenital cutaneous warts experience a spontaneous regression within 2 years; however, some new warts may appear.

• Most patients with EV experience progression of their disease in the third or forth decades of life. Malignant transformation usually arises from actinic keratoses, particularly in patients who are exposed to irradiation. Patients who remain protected from x-rays and sun exposure generally have satisfactory health.

• Genital warts may spontaneously regress, remain unchanged, or increase in size. Treatment of these lesions does not affect the development of cervical cancer.

• Histologic evidence of HPV infection on a cervical Pap smear is similar to mild dysplasia. This subclinical disease often spontaneously regresses.

Patient Education:

• Educating women, particularly those who are socially and economically disadvantaged, about behaviors that enhance sexual risk reduction has a proven benefit in reducing the incidence of STDs. Reducing the incidence of STDs potentially could decrease HPV transmission and, consequently, the incidence of cervical carcinoma.

• For excellent patient education resources, visit eMedicine's Women's Health Center, Pregnancy and Reproduction Center, Cancer and Tumors Center, and Warts Center. Also, see eMedicine's patient education articles Birth Control Overview, Birth Control FAQs, Cervical Cancer, Warts, Genital
  Warts, Plantar Warts, and Pap Smear.

MISCELLANEOUS

Medical/Legal Pitfalls:

• The United States Centers for Disease Control (CDC) has specified Clinical Laboratory Improvement Amendments (CLIA) standards for cytologists to participate successfully in a cytology proficiency testing program to ensure the accuracy of interpretation of Pap smears. These guidelines can be found on the CDC Web site under the CLIA section for Gynecologic Cytology Standards. In order for laboratories in the United States to maintain certification for assessment of Pap smears and other laboratory testing, these standards must be followed.

Special Concerns:

• Pregnancy

• The risk of perinatal HPV transmission to the oropharyngeal mucosa of the neonate is low for mothers with latent infections or genital warts. The time between rupture of the amnion and delivery may be a critical factor in predicting transmission.

• Infants with HPV-positive nasopharyngeal aspirates in the immediate postpartum period are considered contaminated rather than infected with HPV because the virus generally clears from the neonate over several months after birth. Cesarean delivery for the prevention of vertical HPV transmission to the newborn is not indicated. However, in rare cases, cesarean delivery may be indicated if the pelvic outlet is obstructed by large genital warts.

• Sex partners

• Although a high prevalence of HPV-associated penile SILs exists in the male sex partners of women with cervical SILs, examination of these men is not necessary for management of HPV disease. Nevertheless, sex partners of patients with HPV disease may benefit from examination and a detailed evaluation for STDs.

• Condom use may reduce the transmission of HPV to uninfected sex partners, but it does not eliminate the risk. Furthermore, caution patients that treatment does not eliminate the possibility of HPV transmission because latent virus still may be present in tissues adjacent to treated areas.

Ureaplasma Infection

Synonyms and related keywords: Ureaplasma infection, mycoplasma, Mycoplasma pneumoniae, M pneumoniae, Mycoplasma hominis, M hominis, Ureaplasma, Ureaplasma urealyticum, U urealyticum, Ureaplasma parvum, U parvum, Mycoplasma genitalium, M genitalium, Mycoplasma fermentans, M fermentans, Mycoplasma pirum, M pirum, Mycoplasma penetrans, M penetrans, urogenital disease, urethritis, urogenital infection, genital mycoplasmal organisms, ureaplasmas, ureaplasmal infection, cervicitis, pelvic inflammatory disease, PID, pneumonia, bacterial pneumonia, infectious arthritis, nongonococcal urethritis, nonchlamydial nongonococcal urethritis, female urethral syndrome, acute epididymoorchitis, acute pyelonephritis, bacterial vaginosis, salpingitis, congenital pneumonia, congenital bacteremia, congenital meningitis, bronchopulmonary dysplasia, osteomyelitis, meningitis, endometritis, chorioamnionitis, surgical wound infections, neonatal pneumonia, neonatal meningitis, septic arthritis, pneumonitis



INTRODUCTION

Background: Mycoplasma species are the smallest free-living organisms and are unique among prokaryotes in that they lack a cell wall. This feature is largely responsible for their biologic properties, including lack of a Gram stain reaction and nonsusceptibility to many commonly prescribed antimicrobial agents, including beta-lactams. Mycoplasma organisms are usually associated with mucosae. They reside extracellularly in the respiratory and urogenital tracts and rarely penetrate the submucosa, except in the case of immunosuppression or instrumentation, when they may invade the bloodstream and disseminate to numerous organs and tissues.

Among the 17 species isolated from humans, 4 types of organisms are of major concern. Mycoplasma pneumoniae is a well-established pathogen; it is rarely isolated from healthy persons. See Mycoplasma Infections for a discussion of M pneumoniae infection. Mycoplasma hominis and Ureaplasma species, known collectively as the genital mycoplasmal organisms, are generally considered opportunists that cause invasive infections in susceptible populations. The 2 Ureaplasma biovars, Ureaplasma urealyticum and Ureaplasma parvum, have now been designated as separate species. Separation of these species is not possible except via molecular techniques such as polymerase chain reaction (PCR). Therefore, they are considered together as Ureaplasma species (Waites, Clin Microbiol Rev, 2005).

Serologic studies and PCR have enhanced knowledge of several other fastidious and slow-growing mycoplasmal organisms, including Mycoplasma genitalium, Mycoplasma fermentans, Mycoplasma pirum, and Mycoplasma penetrans, and their possible roles in certain pathologic conditions in humans. Because of their extremely fastidious nature and the lack of reliable means for cultivation on artificial media, detection of these mycoplasmal organisms rests primarily with molecular techniques. Relatively little is known about their importance as human pathogens, with the notable exception of M genitalium, an organism that has been the focus of a considerable number of clinical research studies in recent years. This research and the subsequent data are made possible by the availability of PCR assays, which can detect the presence of these organisms.

Pathophysiology: Although M hominis and Ureaplasma species are frequently detected in the lower urogenital tracts of healthy adults, they can also produce localized urogenital diseases. In some settings, they can produce infection in extragenital sites, as does M genitalium. Recent studies with PCR assays expanded the understanding of sites of mycoplasmal localization within the human body. The presence of M fermentans was demonstrated in the throats of children with pneumonia and in the synovial fluid of persons with rheumatoid arthritis. M genitalium is found in the lower urogenital tracts of men with urethritis and women with cervicitis and pelvic inflammatory disease. M penetrans is found in the urine of children and homosexual males infected with HIV, but the clinical significance of this is not known.

No credible evidence indicates that mycoplasmal organisms have a role in the pathogenesis of Gulf War syndrome (Waites, Mycoplasmas: Pathogenesis, Molecular Biology, and Emerging Strategies for Control, 2005).

The newest mycoplasmal species to be detected in humans is Mycoplasma amphoriforme, an organism detected in the lower respiratory tract of immunosuppressed persons with chronic bronchitis (Webster, 2003). Its true role as a human pathogen has not yet been determined.

In humans, both Mycoplasma and Ureaplasma species may be transmitted by direct contact between hosts (ie, venereally through genital-to-genital or oral-to-genital contact), vertically from mother to offspring (either at birth or in utero), or by nosocomial acquisition through transplanted tissues.

Ureaplasma species and M genitalium are causes of nonchlamydial nongonococcal urethritis in men (Waites, Clin Microbiol Rev, 2005; Jensen, 2004). No evidence indicates that that M hominis causes female urethral syndrome; however, Ureaplasma species may be involved. Ureaplasma organisms have been recovered from an epididymal aspirate from a patient with acute epididymoorchitis, and these organisms may be an infrequent cause of the disease. M hominis has been isolated from the upper urinary tract of patients with symptoms of acute pyelonephritis and may cause approximately 5% of cases.

Mycoplasma species do not cause vaginitis, but they may proliferate in patients with bacterial vaginosis and may contribute to the condition. M hominis has been isolated from the endometria and fallopian tubes of approximately 10% of women with salpingitis; M genitalium may also be involved in pelvic inflammatory disease and cervicitis. Whether Ureaplasma infection causes involuntary infertility remains speculative. Ureaplasma species can cause placental inflammation and may invade the amniotic sac early, causing persistent infection and adverse pregnancy outcomes, including premature birth. M hominis has been isolated from the blood of approximately 10% of women with postpartum or postabortal fever, but not from afebrile women who had abortions or from healthy women who are pregnant. Similar observations have been made for Ureaplasma species.

Colonization of infants by genital mycoplasmal organisms may occur by ascension of the microorganisms from the lower genital tract of the mother at the time of delivery or by direct invasion of the fetus in utero. Congenital pneumonia, bacteremia, meningitis, and death have occurred in infants with very low birth weight due to Ureaplasma or Mycoplasma infection of the lower respiratory tract. In several large studies, chronic lung disease of prematurity or bronchopulmonary dysplasia has also been associated with the presence of Ureaplasma organisms in the lower respiratory tract, presumably because of low-grade inflammation in the airways that causes a prolonged need for supplemental oxygen coupled with barotrauma of mechanical ventilation and oxidant damage due to oxygen administration (Waites, Clin Microbiol Rev, 2005).

Both M hominis and Ureaplasma species have been isolated from maternal blood, umbilical cord blood, and neonatal blood. Both organisms can invade the cerebrospinal fluid (CSF) and induce pleocytosis. While M fermentans has been detected in pure culture from placentae and amniotic fluid in the presence of inflammation, no studies confirm its occurrence and significance in neonates.

Both Mycoplasma and Ureaplasma species can cause invasive disease of the joints and respiratory tract with bacteremic dissemination, particularly in persons with antibody deficiencies (Furr, 1994). Ureaplasma species are the most common nonbacterial etiologies of infectious arthritis in persons who are hypogammaglobulinemic. M hominis bacteremia has been demonstrated following renal transplantation, trauma, and genitourinary manipulations. This organism has also been found in surgical wound infections, fluids from pericardial effusions, prosthetic valves affected by endocarditis, and subcutaneous abscesses. Both organisms can cause osteomyelitis. M fermentans, M hominis, and Ureaplasma species can be detected with culture or PCR in the synovial fluid of persons with rheumatoid arthritis. Their precise contribution to this disease is uncertain (Waites, Mycoplasmas: Pathogenesis, Molecular Biology, and Emerging Strategies for Control, 2005).

The significance of M fermentans, M penetrans, M pirum, and other mycoplasmal infections in persons also infected with HIV has received a great deal of attention and is a matter of debate. M fermentans has also been detected in adults with an acute influenzalike illness and in the bronchoalveolar lavage fluids of patients with AIDS and pneumonia. Apparently, respiratory tract infection with M fermentans is not necessarily linked with immunodeficiency, but it may behave as an opportunistic respiratory pathogen.

Frequency:

• In the US: Ureaplasma species have been isolated from cervicovaginal specimens in 40-80% of women who are asymptomatic and sexually active. M hominis has been isolated from cervicovaginal specimens in 21-53% of women who are asymptomatic and sexually active. These rates are somewhat lower in males. Only a subgroup of adults who are colonized in the lower urogenital tract develop symptomatic illness from these organisms. Nongonococcal urethritis is the most common sexually transmitted infection. Ureaplasma species and M genitalium may account for a significant portion of cases that are not due to chlamydiae. More than 20% of liveborn infants may be colonized by Ureaplasma, and infants born preterm most likely harbor the organisms. Colonization declines after age 3 months. Less than 5% of children and 10% of adults who are not sexually active are colonized with genital mycoplasmal microorganisms.

  Immunosuppression (eg, from antibody deficiency or prematurity) increases the likelihood of developing disseminated disease. Much less is known about the epidemiology of species such as M genitalium and M fermentans. Some organisms, such as M pirum and M penetrans, have been primarily isolated from persons with HIV infection.

• Internationally: Although few studies have investigated the geographic distribution of genital mycoplasmal infections, the facts that they (1) are present on mucosal surfaces in so many healthy persons and (2) can be transmitted venereally suggest that variation in prevalence of these organisms in adults is more likely related to behavioral variables such as number of sexual partners and socioeconomic status rather than to geographic or climatic differences.

Mortality/Morbidity:

• Assessing morbidity and mortality for diseases specifically caused by genital mycoplasmal infections is difficult because few studies systematically evaluate them and some conditions with which they are involved can be polymicrobial (eg, pelvic inflammatory disease, urethritis). Difficulty in detecting the more fastidious species, such as M genitalium and M fermentans, further complicates such assessments.

• In adults with an intact and functional immune system, infections associated with genital mycoplasmal organisms are usually localized and do not result in severe illness, attesting to their relatively low virulence and perceived status as opportunists.
  
  
• Persons with antibody deficiencies reportedly have developed severe pulmonary infections, destructive arthritis and osteomyelitis associated with subcutaneous abscesses, and other disseminated infections of various organ systems.
  
  
• Deaths have occurred in neonates with bloodstream invasion by Ureaplasma species and meningitis caused by M hominis; however, in some instances, the organisms spontaneously disappeared from CSF without treatment (Waites, Clin Microbiol Rev, 2005).

• Sporadic case reports document fatal infections caused by Mycoplasma species of animal origin, including Mycoplasma arginini in immunosuppressed hosts, but these are extremely rare (Waites, Mycoplasmas: Pathogenesis, Molecular Biology, and Emerging Strategies for Control, 2005).

Race:

• Differences in carriage of genital mycoplasmal organisms and subsequent disease are more likely related to sexual behavior and socioeconomic status than to race.

Sex:

• No obvious sex predilection is reported for infections due to genital mycoplasmal species, except for the differences in urogenital diseases such as salpingitis and endometritis, which are sex specific. The carriage rate of genital Mycoplasma species in the lower urogenital tract is somewhat greater for females than for males.

• Ureaplasma species have been isolated from cervicovaginal specimens in 40-80% of women who are asymptomatic and sexually active, and M hominis has been isolated from cervicovaginal specimens in 21-53% of women who are asymptomatic and sexually active. This prevalence is somewhat lower in males.

Age:

• M hominis and Ureaplasma species are common commensal inhabitants of the lower genitourinary tract in adolescents and adult men and women who are sexually active. The organisms can be transmitted venereally and vertically from mother to offspring.

• Neonates who acquire the organisms are usually colonized in the upper and sometimes lower respiratory tracts with occasional dissemination to the bloodstream and CSF. Clinically significant infections may ensue in individuals who are sexually active and in neonates but are rare to nonexistent in older children and adolescents who are not sexually active, with the exception of those with immunodeficiencies.

• M fermentans has been recovered from the throats of children with pneumonia; however, the frequency of its occurrence in healthy children is unknown.
  
  
• Little is known about the occurrence of other mycoplasmal species in different populations and specific associations with disease.

CLINICAL

History:

• The clinical history of patients with urogenital or extragenital infections caused by Mycoplasma or Ureaplasma species is syndrome specific, not organism specific, and, as in the case of M pneumoniae respiratory tract infection, no distinguishing features indicate the microbiologic etiology of these conditions.

• Many clinicians are unfamiliar with Mycoplasma and Ureaplasma species as etiologic agents. This unfamiliarity is further complicated by a lack of facilities to diagnose mycoplasmal infections in many clinical settings. Subsequently, identification of these organisms may be achieved only as a last resort, particularly if initial treatment with drugs that are ineffective against Mycoplasma or Ureaplasma species is unsuccessful. The following conditions may be caused by infection with Mycoplasma and Ureaplasma species:

• Urethritis

• Pyelonephritis

• Pelvic inflammatory disease

• Endometritis or chorioamnionitis

• Infectious arthritis

• Surgical wound infections

• Neonatal pneumonia

• Neonatal meningitis

• Mycoplasma and Ureaplasma organisms often play minor roles as causes of the above-named conditions, which may be caused by various microorganisms. When present in patients with some of these conditions, such as salpingitis, urethritis, and septic arthritis, one of several etiologic organisms may be present simultaneously.

Physical:

• Rather than listing the many nonspecific historical and clinical findings of various clinical entities that may be associated with infection with Mycoplasma or Ureaplasma species, emphasizing the need to consider these organisms as potential etiologic agents in the conditions named above is more important in order to perform the necessary diagnostic tests and to provide appropriate antimicrobial treatment that provides coverage for them.

• Consider a Mycoplasma or Ureaplasma infection when persons with hypogammaglobulinemia present with septic arthritis, chronic pulmonary infection, and any other inflammatory condition that does not respond to antimicrobial treatment that is not likely to be effective against these organisms.

• Refer to specific articles on urogenital (eg, Urethritis; Pyelonephritis, Acute; Pyelonephritis, Chronic), obstetric and gynecologic (eg, Pelvic Inflammatory Disease, Endometritis), and neonatal infections (eg, Pneumonia; Meningitis, Bacterial) for additional information regarding history and physical examination findings associated with these conditions.

• Physical presentation in neonates includes the following considerations:

• Neonates, particularly those born preterm, are especially vulnerable to dissemination of infectious organisms (acquired in utero or at birth) in the bloodstream and, ultimately, the CNS.

• Conventional gram-negative and gram-positive bacteria are usually considered the primary culprits of neonatal sepsis; however, when Mycoplasma and Ureaplasma organisms are specifically sought, evidence proves they may be of etiologic significance in neonatal lung disease, bacteremia, and meningitis.

• As with most neonatal infections, no characteristic signs and symptoms predict the type of organism present. Subtle manifestations, such as temperature instability, blood pressure fluctuations, heart rate, and respiratory efforts, may be the only clues that an infection is present.

• Consider Mycoplasma and Ureaplasma species if signs and symptoms of infection are present; if the neonate does not respond to beta-lactam and aminoglycoside drugs; and if cultures from blood, the lower respiratory tract, and CSF do not reveal a more common microbiological etiology.

• Radiographic evidence of pneumonitis in the absence of a proven bacterial or viral etiology and mononuclear or polymorphonuclear pleocytosis of CSF with a negative Gram stain and culture result are consistent with infection associated with M hominis or Ureaplasma species.

Causes:

• The Ureaplasma genus now is subdivided into 2 species: U urealyticum and U parvum. For clinical purposes, separating infections caused by the different 2 species is not possible or necessary. In both the clinical setting and in the diagnostic laboratory, they are considered Ureaplasma species.

DIFFERENTIALS

Chlamydial Genitourinary Infections
Gonococcal Infections

Other Problems to be Considered:

Ureaplasma infections of the urogenital tract and systemic sites may be similar to infections caused by other bacteria and can only be distinguished by appropriate laboratory testing. Specifically, urogenital infections may mimic infections due to gonococci, chlamydiae, or other genital mycoplasmal species.

WORKUP

Lab Studies:

• Perform diagnostic tests for Mycoplasma and Ureaplasma species when a patient presents with a clinical condition known to be caused by or associated with these organisms and when more common etiologies are excluded. The correct microbiological diagnosis takes on greater importance in patients who are immunosuppressed and at greater risk for disseminated infection and a poor outcome.

• Obtain culture results.

• Both M hominis and U urealyticum can be detected in culture within 2-5 days. M genitalium requires a PCR assay.

• Specialized culture media and growth conditions are necessary, and most hospital-based laboratories do not offer these services on-site. Routine bacterial cultures are not sufficient to recover M hominis and cannot detect Ureaplasma species. Detailed laboratory procedures for detection and characterization of genital Mycoplasma and Ureaplasma infections can be found in reference texts (Waites, 2001).

• Specimens can be collected in a specialized liquid transport system, a growth medium designed for mycoplasmal organisms (eg, SP4 broth), or some of the common transport systems for Chlamydia species or other bacteria and shipped frozen to a reference laboratory for testing if necessary. Preventing desiccation and protecting the specimen from adverse temperature extremes is essential if the organisms are to remain viable.

• In men, urethral swabs are preferred over urine samples for detection of genital mycoplasmal infections because the organisms are cell associated. Use calcium alginate swabs, not wooden cotton-tipped swabs, because the latter may inhibit growth of Mycoplasma and Ureaplasma organisms. Prostatic secretions, semen, and urinary calculi can also be cultured.

• For females, urine, cervical swabs, or vaginal swabs are acceptable. Avoid specimens contaminated by lubricants or antiseptics. Urine samples from females are most useful when obtained by catheter or suprapubic aspiration and if the number of organisms is quantitated. Endometrial tissue, tubal samples, or pouch of Douglas fluid can be obtained to confirm a mycoplasmal etiology for pelvic inflammatory disease or postpartum fever. For women with clinical amnionitis, culture amniotic fluid, blood, and placenta.

• Culture of nasopharyngeal, throat, and endotracheal secretions from neonates is appropriate, especially if their birth weight is less than 1500 g and they have clinical, radiographic, laboratory, or other evidence of pneumonia.

• Extragenital or extrapulmonary specimens submitted for culture should reflect the site of infection and disease process. Sterile fluids, including synovial fluid, peritoneal fluid, pericardial fluid, CSF, and blood, are suitable for culture. Bone chips from patients with chronic osteomyelitis without a proven bacterial etiology are also appropriate for culture, as are wound aspirates and tissue collected after biopsy or autopsy. Successful isolation of M hominis and Ureaplasma species from blood can be achieved by inoculating more than 10 mL directly into liquid mycoplasmal growth medium in at least a 1:10 ratio. Smaller volumes can be used for neonates or children.

• Proper specimen collection and handling are of utmost importance in detecting these fastidious organisms. Inquiring about the services of a suitable reference laboratory and maintaining the appropriate specimen transport medium in clinical facilities is worthwhile if Mycoplasma or Ureaplasma infections are frequently encountered. Numerous references describe the optimum conditions for detecting these organisms in culture. Obtain specific instructions from the laboratory when testing is performed.

• Serologic studies are not useful for evaluating genital mycoplasmal infections.

• Molecular techniques are available on a limited basis from research or reference laboratories.

• Molecular techniques such as PCR are not needed when culture is available for M hominis and Ureaplasma species.

• Fastidious slow-growing mycoplasmal species, such as M genitalium and M fermentans, may cause clinically significant illnesses in the respiratory tract, urogenital tract, or other sites. Their presence can be reliably detected only by molecular techniques such as the PCR assay. Seeking molecular techniques for diagnostic purposes is not usually practical because of the difficulty in their detection and the fact that their role in human disease is not well established. A few US laboratories are capable of testing for the presence of M genitalium and M fermentans. Obtain contact information from the author.

Imaging Studies:

• Imaging studies are not usually performed as part of a workup for uncomplicated infections due to Mycoplasma or Ureaplasma. Exceptions include persons who are immunosuppressed and have apparent septic arthritis or suspected pulmonary infection and neonates with clinical evidence of pneumonitis or chronic lung disease of prematurity. In each of these instances, genital Mycoplasma species may be involved.

• CT scanning: Case reports describe neonates with congenital infections in whom intracranial calcifications and necrosis consistent with congenital cytomegalovirus infection were observed, yet the only infectious organism detected was M hominis; thus, in neonates with unexplained neurologic abnormalities and CSF pleocytosis, CT scanning of the head may be useful to further characterize the intracranial pathologic effects.

• Radiography: Radiographic features typical of neonatal pneumonitis caused by chlamydiae and other pathogens are associated with congenital Ureaplasma infection. Infants who are culture-positive in the lower respiratory tract for Ureaplasma species develop radiographic lung findings consistent with bronchopulmonary dysplasia more rapidly than neonates with negative cultures.

Procedures:

• Specimen collection

• Collection of adequate culture specimens from the infected site is of utmost importance if the microbiological diagnosis of an infection due to Mycoplasma or Ureaplasma species is to be determined because none of the clinical manifestations or other laboratory tests is definitive.

• Collection techniques include the following:
  • Lumbar puncture to obtain CSF
  • Arthrocentesis to obtain synovial fluid
  • Tracheal aspiration to obtain lower respiratory tract secretions or tissues
  • Lung biopsy to obtain lower respiratory tract secretions or tissues
  • Bronchoalveolar lavage to obtain lower respiratory tract secretions or tissues
  • Blood collection to detect bacteremia

• The nature of the procedure reflects the infection suspected.

• Severity of illness dictates the extent to which invasive procedures (eg, lumbar puncture, bronchoalveolar lavage, lung biopsy) are necessary.

TREATMENT

Medical Care:

• Successful treatment hinges on promptly considering Mycoplasma and Ureaplasma species as potential etiologic agents, performing proper diagnostic tests for their detection, and providing appropriate antimicrobial coverage.

• Although persons who are immunosuppressed (eg, those with antibody deficiencies) are rarely encountered in some practices, such individuals may have a disproportionately high frequency of serious infections caused by Mycoplasma and Ureaplasma species; therefore, always consider these organisms in the patient's differential diagnosis.

• Handle medical treatment according to the patient involved, the presence of underlying disease or immunodeficiency, and whether the infection is localized or disseminated. Key to providing pathogen-specific management is obtaining adequate material for microbiologic diagnosis and properly handling this material once it is collected.

• Choose general treatment guidelines for conditions such as acute salpingitis, endometritis, pyelonephritis, urethritis, septic arthritis, neonatal pneumonia, and other conditions associated with or attributed to genital Mycoplasma species according to standard care practices for the various clinical syndromes.

• Other than providing specific antimicrobial agents to cover Mycoplasma and Ureaplasma species, no other unique aspects to the management of these conditions are beneficial.

• Note that Mycoplasma and Ureaplasma organisms are often opportunists and may be present simultaneously with other pathogens in many of the above-described conditions. Treatment decisions should reflect this possibility.

MEDICATION

An oral tetracycline administered for at least 7 days historically has been the DOC for urogenital infections due to M hominis, but resistance now occurs in 20-40% of isolates. A recent survey detected tetracycline resistance in 455 of Ureaplasma isolates, indicating that the susceptibility of these organisms can no longer be assumed (Waites, Clin Microbiol Rev, 2005). The degree of resistance may vary according to geographic area, patient population, and previous exposure to antimicrobial agents. If tetracyclines are relied upon as first-line drugs, consider alternative agents in the event of treatment failures. In vitro susceptibility testing is sometimes indicated for Mycoplasma species recovered from a normally sterile body site, from hosts who are immunocompromised, or from persons who have not responded to initial treatment.

Clindamycin is an alternative treatment for tetracycline-resistant M hominis but is much less effective against Ureaplasma species. Erythromycin or tetracyclines are the DOCs for Ureaplasma infections. Although tetracycline resistance is described in Ureaplasma species, high-level erythromycin resistance does not occur. A single 1-g dose of azithromycin is approved for treatment of urethritis due to Chlamydia trachomatis and works as well clinically as 7 days of doxycycline in persons with urethritis due to Ureaplasma species.

Clarithromycin, although active against Ureaplasma species in vitro at concentrations comparable to or lower than erythromycin, has not been approved for use in the treatment of urogenital infections. M hominis is resistant to erythromycin, azithromycin, and clarithromycin. Despite apparent in vitro susceptibility of Ureaplasma species to tetracycline or erythromycin, treatment of vaginal organisms with these agents is not always successful.

Fluoroquinolones are useful alternatives for treatment of certain infections caused by M hominis or Ureaplasma species within the urogenital tract and in some extragenital locations. Activity of quinolones is not affected by tetracycline resistance, making these drugs attractive alternatives for tetracycline-resistant M hominis or Ureaplasma infections. Newer agents (eg, levofloxacin and moxifloxacin) have the greatest in vitro potency, but scant clinical data are available. In general, M hominis is more susceptible to quinolones in vitro than Ureaplasma species based on minimal inhibitory concentrations. Recent reports have documented fluoroquinolone resistance among M hominis and Ureaplasma species in the United States, France, and China, but the extent to which this occurs is unknown (Bebear, 2000; Duffy, 2006).

Most clinical trials for treatment of genitourinary infections focus primarily on other pathogens, such as C trachomatis and Neisseria gonorrhoeae. Few studies include microbiologic data specific to genital Mycoplasma species, and no systematic comparative evaluations have been performed on treatment regimens for extragenital infections in adults or infections in neonates.

Treatment recommendations, including dosage and duration of therapy, are based largely on in vitro susceptibility data, outcomes of treatment trials evaluating clinical response to syndromes such as pelvic inflammatory disease and urethritis that may be due to genital Mycoplasma, and individual case reports. For infections such as urethritis that may be transmitted venereally, sexual contacts of the index case should also receive treatment.

Experience with Mycoplasma or Ureaplasma infections in patients who are immunocompromised, especially those with hypogammaglobulinemia (who have been studied most extensively), demonstrates that although Mycoplasma species are primarily noninvasive mucosal pathogens in healthy hosts, they have the capacity to produce destructive and progressive disease. Infections may be caused by resistant organisms refractory to antimicrobial therapy and may require prolonged administration of a combination of intravenous antimicrobials for several weeks or even months, intravenous immunoglobulin, and antisera prepared specifically against the infecting species. Even with aggressive therapy, relapses are likely. Repeat cultures of affected sites may be necessary to gauge in vivo response to treatment.

Isolation of M hominis or Ureaplasma species from neonatal pericardial fluid; pleural fluid; tracheal aspirate in association with respiratory disease; abscess material; CSF from those with pleocytosis, progressive hydrocephalus, or other neurologic abnormality; or blood justifies specific treatment in neonates who are critically ill when no other verifiable microbiologic etiologies of the clinical condition are apparent. Whether treatment should be given for a positive CSF culture when inflammation or other evidence of clinical illness is not observed should be handled on a case-by-case basis. Monitoring the patient, repeating the lumbar puncture, and reexamining for inflammation and organisms may be appropriate before initiating treatment because some cases may resolve spontaneously without intervention.

Parenteral tetracyclines are used most often to treat neonatal meningitis caused by either M hominis or Ureaplasma species, despite contraindications. Erythromycin for Ureaplasma species, clindamycin for M hominis, or chloramphenicol for either species are alternatives. Treatment of ureaplasmal respiratory infections in neonates with erythromycin may be effective in eradicating the organisms from the lower airways, but treatment failures are known to occur (Waites, Clin Microbiol Rev, 2005; Waites, 1994). No single drug is successful in every instance for eradication of these organisms from the CSF of neonates. Little clinical experience is available with new-generation macrolides in the treatment of neonatal Ureaplasma infections, and no guidelines for their dosages or use in neonates are available.

Overall treatment alternatives for neonates are the same as for urogenital and systemic mycoplasmal infections in adults, with appropriate dosage modifications based on weight, except that the intravenous route should be used for serious systemic infections. Duration of treatment and drug dosages for neonatal mycoplasmal infections have not been evaluated critically, but a minimum duration of 10-14 days is suggested based on experience in individual cases when microbiologic follow-up care has been assessed.

No clinical data are available for guidance of therapeutic interventions for infections when other mycoplasmal species may be involved; however, M fermentans has in vitro susceptibilities comparable to M hominis, demonstrating some degree of resistance to macrolides and susceptibility to clindamycin.

M genitalium is usually susceptible in vitro to macrolides, tetracyclines, and fluoroquinolones. Azithromycin has been recommended as a treatment alternative for M. genitalium urethritis in view of clinical failures with the tetracyclines. However, a recent case report of azithromycin treatment failure with documentation of elevated minimal inhibitory concentrations (MICs) to this drug in a clinical isolate that responded to a fluoroquinolone (moxifloxacin) indicates that these types of infections can be difficult to manage (Bradshaw, 2006).

Drug Category: Antimicrobial agents -- Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

Drug Name	Erythromycin (E.E.S., E-Mycin, Eryc) -- Inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. Does not affect M hominis.
Adult Dose	250-500 mg PO/IV q6h
Pediatric Dose	20-50 mg/kg/d PO divided tid/qid 25-40 mg/kg/d IV divided qid
Contraindications	Documented hypersensitivity
Interactions	Coadministration may increase toxicity of theophylline, digoxin, carbamazepine, and cyclosporine; may potentiate anticoagulant effects of warfarin; coadministration with lovastatin and simvastatin increases risk of rhabdomyolysis
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in liver disease; estolate formulation may cause cholestatic jaundice; adverse GI effects are common (administer doses pc); discontinue use if nausea, vomiting, malaise, abdominal colic, or fever occurs

Drug Name	Clarithromycin (Biaxin) -- Inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. Does not affect M hominis. No data support use in urogenital infections.
Adult Dose	250-500 mg PO q12h
Pediatric Dose	15 mg/kg/d PO q12h
Contraindications	Documented hypersensitivity; coadministration of pimozide
Interactions	Toxicity increases with coadministration of fluconazole and pimozide; effects decrease and adverse GI effects may increase with coadministration of rifabutin or rifampin; may increase toxicity of anticoagulants, cyclosporine, tacrolimus, digoxin, omeprazole, carbamazepine, ergot alkaloids, triazolam, and HMG CoA-reductase inhibitors; serious cardiac arrhythmias may occur with coadministration of cisapride; plasma levels of certain benzodiazepines may increase, prolonging CNS depression; arrhythmias and increase in QTc intervals occur with disopyramide; coadministration with omeprazole may increase plasma levels of both agents
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Coadministration with ranitidine or bismuth citrate not recommended with CrCl less than 25 mL/min; administer half dose or increase dosing interval if CrCl less than 30 mL/min; irritative diarrhea and superinfections may occur with prolonged or repeated antibiotic therapies

Drug Name	Azithromycin (Zithromax) -- Treats mild-to-moderate microbial infections. IV formulation not recommended for children. Does not affect M hominis. No clinical data are available to support dosage or use in neonates.
Adult Dose	500 mg PO on d 1, then 250 mg PO qd days 2-5 500 mg/d IV for 2 d, then 500 mg PO qd; a single 1-g dose is used for urethritis
Pediatric Dose	10 mg/kg/d PO on d 1, then 5 mg/kg/d PO d 2-5
Contraindications	Documented hypersensitivity; hepatic impairment; coadministration with pimozide
Interactions	Effects are reduced with coadministration of aluminum and/or magnesium antacids; nephrotoxicity and neurotoxicity may occur when coadministered with cyclosporine
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	May increase toxicity of theophylline, warfarin, and digoxin; effects are reduced with coadministration of aluminum and/or magnesium antacids; nephrotoxicity and neurotoxicity may occur when coadministered with cyclosporine; nausea and vomiting or irritative diarrhea may occur

Drug Name	Clindamycin (Cleocin) -- Inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. Does not affect Ureaplasma.
Adult Dose	150-450 mg PO q6h 150-900 mg IV q6-8h
Pediatric Dose	Neonates: Not to exceed 15-20 mg/kg/d divided tid/qid 10-25 mg/kg/d PO divided tid/qid 10-40 mg/kg/d IV divided tid/qid
Contraindications	Documented hypersensitivity; regional enteritis; ulcerative colitis; severe hepatic impairment; antibiotic-associated colitis
Interactions	Increases duration of neuromuscular blockade induced by tubocurarine and pancuronium; erythromycin may antagonize effects of clindamycin; antidiarrheals may delay absorption of clindamycin
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Adjust dose in severe hepatic dysfunction; no adjustment necessary in renal insufficiency; associated with severe and possibly fatal colitis

Drug Name	Doxycycline (Vibramycin, Bio-Tab, Doryx) -- Inhibits protein synthesis and thus bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria. Some M hominis strains and Ureaplasma species may be resistant.
Adult Dose	100 mg PO/IV q12h
Pediatric Dose	Not recommended for use in children; if no alternative, 2-4 mg/kg/d IV/PO or divided bid recommended
Contraindications	Documented hypersensitivity; severe hepatic dysfunction
Interactions	Bioavailability decreases minimally with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; tetracyclines can increase hypoprothrombinemic effects of anticoagulants; tetracyclines can decrease effects of PO contraceptives, causing breakthrough bleeding and increased risk of pregnancy
Pregnancy	D - Unsafe in pregnancy
Precautions	Photosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; tetracycline use during tooth development (last half of pregnancy through 8 y) can cause permanent discoloration of teeth; Fanconilike syndrome may occur with outdated tetracyclines

Drug Name	Levofloxacin (Levaquin) -- Inhibits DNA gyrase and prevents DNA replication.
Adult Dose	500 mg/d PO/IV for 7-14 d
Pediatric Dose	less than 18 years: Not recommended >18 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2 h before or 4 h after taking fluoroquinolones; cimetidine may interfere with metabolism; reduces therapeutic effects of phenytoin; probenecid may increase serum concentrations
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Adjust dose in renal function impairment

Drug Name	Ofloxacin (Floxin) -- Inhibits DNA gyrase and topoisomerase IV and prevents bacterial DNA replication.
Adult Dose	200-400 mg PO/IV q12h
Pediatric Dose	less than 18 years: Not recommended >18 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2 h before or 4 h after taking fluoroquinolones; cimetidine may interfere with metabolism; reduces therapeutic effects of phenytoin; probenecid may increase serum concentrations; may increase toxicity of theophylline, caffeine, cyclosporine, and digoxin (monitor digoxin levels); may increase effects of anticoagulants (monitor PT)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	In prolonged therapy, perform periodic evaluations of organ system functions (eg, renal, hepatic, hematopoietic); adjust dose in renal function impairment (if CrCl is less than 50 mL/min, dosage reduction may be necessary); superinfections may occur with prolonged or repeated antibiotic therapy

Drug Name	Chloramphenicol (Chloromycetin) -- Binds to 50S bacterial ribosomal subunits and inhibits bacterial growth by inhibiting protein synthesis.
Adult Dose	50-100 mg/kg/d IV divided qid
Pediatric Dose	Neonates less than 2 weeks: 25 mg/kg/d in 1 dose >2 weeks: 25-100 mg/kg/d IV divided qid
Contraindications	Documented hypersensitivity
Interactions	Concurrent administration with barbiturates may decrease serum levels, while barbiturate levels may increase (causing toxicity); manifestations of hypoglycemia may occur with sulfonylureas; rifampin may reduce serum levels, presumably through hepatic enzyme induction; may increase effects of anticoagulants; may increase serum hydantoin levels, possibly resulting in toxicity (chloramphenicol levels may be increased or decreased)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Use only for serious infections; serious and fatal blood dyscrasias (aplastic anemia, hypoplastic anemia, thrombocytopenia, granulocytopenia) can occur; discontinue upon appearance of reticulocytopenia, leukopenia, thrombocytopenia, anemia, or findings attributable to chloramphenicol; adjust dose in liver or kidney dysfunction; caution in pregnancy at term or during labor because of potential toxic effects on fetus (gray syndrome)

Drug Name	Minocycline (Dynacin, Minocin) -- Treats infections caused by susceptible gram-negative and gram-positive organisms. Some M hominis strains and Ureaplasma species maybe resistant.
Adult Dose	100 mg PO bid
Pediatric Dose	less than 8 years: Not recommended >8 years: 4 mg/kg PO initially, followed with 2 mg/kg q12h
Contraindications	Documented hypersensitivity; severe hepatic dysfunction
Interactions	Bioavailability decreases with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; can decrease effects of PO contraceptives, causing breakthrough bleeding and increased risk of pregnancy
Pregnancy	D - Unsafe in pregnancy
Precautions	Reduce dose in renal impairment; tetracycline use during tooth development (last half of pregnancy through 8 y) can cause permanent discoloration of teeth

FOLLOW-UP

Deterrence/Prevention:

• Because of the frequency with which genital Mycoplasma and Ureaplasma organisms are carried in the lower urogenital tract in persons who are asymptomatic and sexually active, use of barrier protection methods (eg, condoms) is of little benefit because the organisms most often act as opportunistic normal florae.

• Delivery of infants by cesarean delivery has not prevented colonization in the lower respiratory tract because acquisition of the organisms can occur in utero by ascending infection, even through intact fetal membranes.

• Although no systematic studies have been performed, the epidemiology of these organisms suggests that persons who are sexually inactive do not usually harbor them and, therefore, cannot be expected to develop clinically significant infections. Abstinence may prevent spread of the organisms among adolescents and adults.

MISCELLANEOUS

Medical/Legal Pitfalls:

• In general, infection with Mycoplasma and Ureaplasma species is limited to mucosal surfaces of the lower urogenital tract. In otherwise healthy persons, these infections are associated with relatively low morbidity rates. However, in individuals who are immunosuppressed, including preterm neonates, invasive infections of various organ systems can occur, including bones, joints, and the CNS. Failure to properly diagnose such systemic infections and to administer appropriate antimicrobial therapy can be associated with poor outcomes and chronic debilitation.