Gonococcal Infections in Neonates and Young Children

Gonococcal Infections in Neonates and Young Children Charles R. Woods, MD, MS Gonorrhea has been recognized since antiquity, and more than 60 million new cases occur yearly worldwide. Much has been learned about the molecular pathogenesis of infection by Neisseria gonorrhoeae, but immunity from natural infection does not protect against reinfection with the same strain, and the goal of a protective vaccine remains elusive. Gonococcal ophthalmia neonatorum is the most common manifestation in infants born to mothers with gonococcal genital tract infections. Genital and pharyngeal gonococcal infections in young children almost always are acquired from sexual abuse by an infected adult. Invasive disease can occur at any age but is uncommon. Nonculture diagnostic tests are widely used in adults, but culture is required in children for medicolegal purposes. N. gonorrhoeae strains have developed resistance to many antibiotic classes, and resistance profiles vary among geographic regions and within regions over time. Current guidelines for treatment of gonococcal infections in children in the United States are reviewed. Semin Pediatr Infect Dis 16:258-270 © 2005 Elsevier Inc. All rights reserved.

G

Epidemiology of Gonococcal Infection

Department of Pediatrics, Wake Forest University School of Medicine, Winston-Salem, NC. Address reprint requests to Charles R. Woods, Department of Pediatrics, Wake Forest University School of Medicine, Winston-Salem, NC 27157. E-mail: [email protected]

Rates of gonococcal infections in the United States (Fig. 1) and Western Europe have declined in the past 20 years, but an estimated 62.35 million new cases of gonococcal infections occurred worldwide in 1999, almost half of which were in South and Southeast Asia and another quarter in subSaharan Africa.6 In 2003, 335,104 cases were reported in the United States, yielding a rate of 116.2/100,000 population.7 The Healthy People 2010 national goal in the United States is 19 per 100,000. Gonococcal infections remain second only to chlamydia infections in incidence among reportable diseases.8 Females 15 to 19 and 20 to 24 years old had the highest rates of infection at 635 and 595 per 100,000, respectively, in 2002. Case fatalities for gonococcal infections are rare occurrences: approximately four deaths were reported per year (due to gonococcal sepsis) in the United States from 1989 to 1998.4,5,9,10 Gonococcal rates generally are higher in southeastern states than in other regions of the country (Fig. 2). Rates among African Americans are greater than four-fold higher than those of White-non-Hispanics and Latinos.7 Low socioeconomic status, early onset of sexual activity, unmarried marital status, and past gonococcal infections are risk factors for acquisition of gonococcal infection, as are prostitution and illicit drug use.11,12 Areas with higher rates of adult disease have higher numbers of pediatric cases,13,14 reflecting the adult origin of virtually all pediatric cases. Incidence is

onorrhea is one of the oldest known human diseases, described by Hippocrates in the fifth century B.C. and given its current name, meaning “flow of semen,” by Galen in the second century A.D. Sexual activity was recognized as a risk factor early on, and Greco-Roman physicians prescribed sexual abstinence and washing of the eyes of newborns as treatments. Neisseria gonorrhoeae was identified in stained smears of exudates by Albert Neisser in 1879. The availability of sulfonamides in 1936 and then penicillin in 1943 represented major advances in combating gonorrhea.1,2 Reproductive sequelae of infection after puberty (eg, infertility) and continuously emerging resistance to new classes of antimicrobial agents have kept gonococcal infections at the forefront as a global public health problem.3-5 This review focuses on manifestations of gonococcal infection in neonates and young children. Ophthalmia neonatorum is the primary gonococcal infection in infants. In prepubertal children, gonococcal infection usually involves the lower genital tract and almost always is transmitted by sexual contact. Gonococcal infections in adolescents are similar to those in adults and have been reviewed recently in the July 2005 issue of Seminars in Pediatric Infectious Diseases.

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Gonococcal infections in neonates and young children

259 cent.19,20 Fomite transmission generally is highly unlikely to occur because gonococci can survive for only minutes outside the human body. Viable organisms have been recovered from environmental sources (eg, toilet seats) for up to 3 hours after artificial inoculation in large numbers, but not from random samplings in public restrooms.21

Microbiology

Figure 1 Gonorrhea rates, United States, 1970 to 2003. The Healthy People 2010 objective for gonorrhea is 19 cases per 100,000 population. From Centers for Disease Control and Prevention.5

more common among girls than boys. Rates of gonorrhea are based primarily on the detection of symptomatic infection. Asymptomatic chronic infection in adults may account for 5 percent of cases. Asymptomatic infection also can occur in prepubertal children.15-18 Humans are the only reservoir of N. gonorrhoeae. Exudate and secretions from infected mucosal surfaces allow transmission during the intimate contacts of sexual acts, vaginal birth, and, perhaps rarely, household exposures. The incubation period usually is 2 to 7 days. The risk of male urethral infection developing after a single episode of vaginal intercourse with an infected female is approximately 20 percent and increases to 60 to 80 percent with four exposures. Prevalence of infection among female sexual contacts of males with gonococcal urethritis can range from 50 to 90 per-

Neisseria spp. are aerobic, gram-negative, nonmotile, and nonsporeforming. Gonococci occur in pairs (diplococci), with adjacent sides flattened, and have an outer membrane overlying a thin peptidoglycan layer and cytoplasmic membrane that is typical of gram-negative bacteria. The species lacks a true polysaccharide capsule but produces a surface polyphosphate that provides a hydrophilic, negatively charged surface.22 The microbes frequently are seen within phagocytes in Gram stains of clinical specimens. Neisseria require enriched media (eg, chocolate blood agar), including free iron, to support their growth, which is optimal in a 5 percent CO2 atmosphere at 35 to 37°C and pH 6.5 to 7.5. Gonococci do not survive below pH 6.0 or above 40°C and grow poorly below 30°C. Under low-power microscopy, some colonies appear opaque or granular, whereas others are transparent. The former represent colonies where most cells express one or more opacity-associated proteins (Opa), whereas most of those in transparent colonies do not.23-25 N. gonorrhoeae has a typical prokaryotic circular chromosome that is approximately 2154 kb in size, approximately half that of Escherichia coli.26 The genome of N. gonorrhoeae

Figure 2 Gonorrhea rates by state, United States and outlying areas, 2003. The total rate for the United States (including the outlying regions of Guam, Puerto Rico, and the Virgin Islands) in 2003 was 114.7 per 100,000 population. From Centers for Disease Control and Prevention.5

C.R. Woods

260 strain FA1090 has been sequenced. Gonococci are highly autolytic and release DNA in a biologically active form that can be taken up readily by, or exchanged with, other strains. This property allows the genetic and phenotypic diversity that helps to maintain this species among its human hosts and facilitates transfer of chromosomal antibiotic-resistant genes.27 A 36-kb conjugal plasmid is present in many gonococci. It is able to mobilize its own transfer as well as that of other nonself-mobilizable plasmids (eg, the 4.5- and 7.5-kb penicillinase plasmids).28,29

Pathogenesis Gonococci are able to survive in the urethra in the face of hydrodynamic forces that tend to wash other microbes away, suggesting an ability to adhere to mucosal epithelial cells. They are able to persist despite generating an intense influx of neutrophils, which indicates capacity to evade the host acute innate immune response. Individuals also can have repeated infections with the same gonococcal strain, suggesting the occurrence of frequent antigenic variations that thwart established local immune responses. Tissue damage that occurs in the fallopian tubes during salpingitis implies the presence of at least one factor that is directly toxic or that can trigger a deleterious host response.30,31 After adhering to host epithelial cells, individual gonococci invade (are engulfed), replicate intracellularly inside phagosomes, and exit the basal (but not lateral) surface of the cell into the submucosal space via exocytosis.32,33 Adjacent nonepithelial cells may be sloughed, likely due to toxic effects of microbial lipo-oligosaccharide and peptidoglycans.31 The mucosal epithelial damage and submucosal invasion result in a chemotactic influx of neutrophils. This dynamic leads to formation of microabscesses and exudation of purulent material into the lumen (or surface) of the infected tissues. The vast majority of gonococcal cells are ingested by neutrophils and killed,34 as gonococci are susceptible to the oxidative burst products and also can be killed efficiently by nonoxidative products such as cathepsin G.35 A minority of cells escape the innate and early adaptive immune responses, such that infection and contagion can persist for weeks to months if untreated. Adherence of gonococci to epithelial cells induces activation of nuclear factor kappa B and activator protein 1, which leads to upregulation of mRNAs and release of numerous cytokines and chemokines: macrophage-colony stimulating factor, tumor necrosis factor-␣ (TNF␣), tumor growth factor ␤, monocyte chemoattractant protein 1, and inteleukins-1␤, ⫺6, and – 8. Intraurethral challenge leads to increased levels of IL-8, IL-6, and TNF␣ in urine before onset of symptoms and in plasma at the onset of symptoms.36,37 N. gonorrhoeae strains have a number of characteristics that appear to play key roles in virulence (Table 1). Among these are pili, opacity proteins, porin protein, ability to survive in low-iron environments, IgA protease, the lipo-oligosaccharide, the cell wall peptidoglycan, reduction modifiable protein, and Ribosomal protein L12. This list likely will expand

as the roles of other recently identified gonococcal gene products and molecular systems are elucidated further.31,32,38-52 Strains of N. gonorrhoeae from adults (and probably children) with disseminated disease often differ from strains causing local genital infection. These strains usually 1) are less susceptible to the bactericidal activity of sera; 2) do not express Opa proteins; 3) require the presence of arginine, uracil, and hypoxanthine (labeled the AHU- auxotroph), which is not the case for most other strains; 4) retain a high degree of sensitivity to penicillin; and 5) are susceptible to vancomycin, which may prevent their detection in selective media but not in the usual media used for blood cultures.53-55 Although the host immune response is robust and ultimately clears the infection, protective immunity is not induced by genital or mucosal infection. Reinfection by the same serovar or strain is a common occurrence.56,57 Inherited or acquired complement deficiencies may predispose to disseminated gonococcal infection (as with meningococcal disease). Approximately 13 percent of patients with disseminated disease have complement deficiencies.58

Perinatal Gonococcal Infections Among pregnant women with gonococcal infection, 13 percent will experience septic abortion, 23 percent will deliver prematurely (approximately one-third of these infants will die), and 29 percent will have premature rupture of the membranes. Recognition of gonorrhea early in pregnancy identifies a population at risk that should be followed for potential reinfection throughout pregnancy.59,60 Adolescent girls have a higher prevalence of gonorrhea than do older women of childbearing age, which likely translates into higher rates of gonorrhea in pregnant adolescents. Rates of gonococcal infection in neonates reflect the prevalence of infection among pregnant women. The most common manifestation of gonococcal infection in the neonatal period is gonococcal ophthalmia neonatorum (GON). Scalp abscesses, other wound infections, and systemic disease (sepsis, meningitis) also can occur. Neonatal vulvovaginitis, proctitis, rhinitis, funisitis, and urethritis have been described but are infrequent findings.61 Gonococcal colonization of the oropharynx and/or gastric fluid occurs relatively frequently in perinatally exposed infants.62 The incidence of neonatal gonococcal colonization and disease in N. gonorrhoeaeexposed infants is provided in Table 2.

Gonococcal Ophthalmia Neonatorum Prevention For centuries, ophthalmia neonatorum has been known to occur in infants born to women with a vaginal discharge. Instillation of 2 percent silver nitrate (AgNO3) into the infant’s conjunctival sac as preventive treatment for GON was described by Dr. Carl Sigmund Franz Credé in 1881.63 In the United States, prophylaxis for GON is recommended for all infants immediately after birth and is required by law in most states. Prophylaxis regimens using 1 percent solution of AgNO3, 1 percent tetracycline ointment, or 0.5 percent

Virulence Factor

Host Cell Interactions

Interaction Results

Other Functions/Characteristics

release and cytoskeletal rearrangements that lead to elongation of microvilli which embrace the microbe, facilitating cell entry.

Provides twitching motility function. Involved in DNA transformation. Undergoes phase variation. May play a role in resistance granulocyte phagocytosis.32 Undergo antigenic and phase variations. Sequesters pyruvate kinase while within host cells to acquire pyruvate for bacterial metabolic needs.40 Can induce apoptosis in epithelial cells and neutrophils in vitro.42 Located in the cell membrane in close proximity to lipo-oligosaccharides and reduction modifiable proteins. Allows small molecules to pass through the bacterial outer cell membrane. Gonococci do not produce any siderophores. Transferrin- and lactoferrin-binding proteins are required in order for gonococci to cause experimental urethritis.46

Pili

Pilus PilC protein subunit binds to CD46* receptors that are present on most human cells38

Calcium24

Opacity-associated proteins (Opa; each strain can make at least 10 different types, but express no more than five at a time) Porin protein (most common outer membrane protein; exists as a trimer in the membrane)

Most interact with the CD66 (CEACAM) family of receptors on epithelial cells and neutrophils. Translocates into the host cell membrane. Able to bind with C4b-binding protein.41

Mediates nonopsonic phagocytosis by neutrophils that is distinct from antibody- and complementmediated phagocytosis.32, 39

Iron-scavenging system of proteins45

Scavenges iron from transferrin, lactoferrin, and hemoglobin

Allows microbe to maintain metabolic processes in the face of the low free iron environment created by early innate immune responses.

IgA protease

Cleaves IgA, at the hinge region. Cleaves host cell lysosome-associated membrane protein, which is involved in phagosome compartmentalization.47 LOS moieties mimic human glycosphingolipids; can bind to asialoglycoprotein receptor (ASGP-R). Induces cytokine production (TNF-␣ IL-1␤, IL-6, IL-8) from urethral epithelial cells.49

May help to evade host IgA at the mucosal surface. Most important function may be to enhance intracellular survival within host cell phagosomes.

Lipo-oligosaccharide (LOS; up to six variants expressed by a single strain48)

Cell wall peptidoglycan (shed as membrane fragments during exponential growth) Reduction modifiable protein (Rmp)

Ribosomal protein L12

Translocation permits a rapid Ca2ⴙ influx into the host cell from the external environment.42 Disrupts neutrophil degranulation, oxidative burst, and phagosome maturation.43, 44 Down-regulation of complement activation.

Can activate the classic complement pathway. Can mediate host defensin-enhanced adherence to epithelial cells.50 ASGP-R interaction mediates endocytosis (internalization of the micobe into epithelial cells). Activation of complement occurs. Modulation of mononuclear cell proliferation.

Generates host antibodies against itself.

Antibodies that bind to Rmp epitopes block the bactericidal effect of complement-fixing IgM antibodies that recognize LOS.

Binds to lutropin receptors in the upper female genital tract.

Facilitates ascending infection in females.

Consists of a lipid A moiety and a core polysaccharide; lacks the long polymeric sugars lipopolysaccharides. Predominately short LOS appear more sensitive to killing by human serum but also more able to invade eukaryotic cells. Cause damage to fallopian tube mucosal cells in organ culture.31 Women with preexisting anti-Rmp antibodies appear more susceptible to infection than those without such antibodies.51 Ribosomal protein L12 mimics the structure of human chorionic gonadotropin, which is the natural ligand for lutropin receptor.40,52

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*CD46 molecules serve as receptors for C3b, C4b, measles, and other viruses.

Gonococcal infections in neonates and young children

Table 1 Selected Virulence Factors of Neisseria gonorrhoeae

C.R. Woods

262 Table 2 Incidence of Neonatal Gonococcal Infections Among Infants Born to Mothers With Gonococcal Infection Site of Involvement Conjunctival infection Orogastric fluid colonization Oropharyngeal colonization Disseminated disease (as a proportion of all neonatal gonorrhea)

Rate of Positive Cultures 0–10% 2–48% 26–40% 35% 0–1%(rare)

Population of Infants Exposed infants who received silver nitrate ocular prophylaxis. Exposed infants who did not receive ocular prophylaxis. Infants of mothers with gonococcal infection. Infants with gonococcal ophthalmia Infants with gonococcal infection

Modified from Woods C.79

erythromycin ophthalmic ointment are considered equally effective. Each is available in single-dose units, which are preferred over multidose tubes. One of these agents should be instilled into the eyes of every neonate within 1 hour after birth. Povidone-iodine 2.5 percent solution also appears effective (and perhaps more effective for Chlamydia trachomatis)64 but is not recommended at this time in the United States.65 The major advantages to the use of AgNO3 for prophylaxis are very low cost, lack of allergic potential, and absence of bacterial resistance to the compound. Disadvantages include development of conjunctival irritation with associated exudate in many babies and failure if gonococcal infection of the eye began before birth. The chemical conjunctivitis that can result from AgNO3 prophylaxis typically starts within 6 to 24 hours after administration and disappears within 24 to 48 hours. AgNO3 will not prevent progression of established infection. Premature rupture of membranes is associated with increased risk of developing GON. In rare cases, active GON can be present at the time of birth. The occasional failure of AgNO3 prophylaxis emphasizes that it is preferable to prevent GON through identification and treatment of the pregnant woman. Because of the potential failure of prophylaxis in established infection, infants born to mothers with known gonococcal infections should be treated with a single parenteral dose of a third-generation cephalosporin (see Treatment section below). Clinical Features of GON Although frequently mild, infection of the eye of the newborn with N. gonorrhoeae can be rapidly destructive and lead to corneal scarring and blindness. Colonization during delivery is followed by an incubation period of 2 to 5 days (usually ⬍3 days), but cases may arise 2 to 3 weeks after delivery.66 The disease usually is bilateral and begins with prominent eyelid edema, followed by chemosis (Fig. 3). The discharge initially may be watery but progresses to prominent mucopurulence within a short time and may contain blood (from superficial hemorrhage). Corneal ulceration ensues in severe cases, and perforation of the globe and panophthalmitis can occur. Rapid arrest of the disease is essential to assure that vision is preserved. The conjunctivae occasionally serve as a portal of entry for gonococcal septicemia, arthritis, and/or other manifestations of invasive disease. Some cases of GON are selflimited, and most have a benign outcome with treatment.61

In the United States, the recommendation is that blood and cerebrospinal fluid cultures be obtained in infants with GON (or any other type of gonococcal infection) and that these infants be hospitalized, at least initially, for treatment.65 Some experts consider evaluation for meningitis unnecessary in an otherwise well-appearing infant with GON.59 Other microbes that are potential causes of neonatal conjunctivitis include Haemophilus influenzae (nontypeable strains), Streptococcus pneumoniae, Staphylococcus aureus, Neisseria cinerea, Klebsiella pneumoniae, enterococci, Chlamydia. trachomatis, herpes simplex viruses, and adenoviruses.14,67 Conjunctivitis as the result of these causes usually is mild and less rapidly progressive than is GON.

Gonococcal Scalp Abscess Gonococcal infections of the minor scalp wounds incurred with fetal monitoring are not unusual findings in infants whose mothers harbor the microbe.68 Necrosis and scalp abscess can occur, and these sites can be a focus for disseminated infection. Scalp wounds in neonates should be cultured for gonococci as well as for other likely pathogens, which include Staphylococcus spp., group B streptococci, H. influenzae, and gram-negative enteric flora. Herpes simplex virus also may infect areas of injury to the scalp of newborns.

Figure 3 Gonococcal ophthalmia neonatorum. The usual clinical presentation is bilateral conjunctivitis that becomes progressively purulent if untreated. From Gutman LT.61

Gonococcal infections in neonates and young children

Systemic Disease in the Neonate Disseminated disease occurs in 1 percent or fewer of infants perinatally exposed to gonococcal infection.69 Septic arthritis (usually without other disease manifestations) is the most common form of disseminated gonococcal infection found in neonates. Clinical findings usually occur in infants from 1 to 4 weeks of age. Signs and symptoms of gonococcal septic arthritis are similar to those of joint infections caused by other microbes in the neonatal period, including a predominance of polyarticular involvement. Infection involves most frequently the ankles, knees, wrists, and hands.70 Leukocytosis is a typical finding, and most infants have a positive culture and compatible Gram stain from the synovial fluid of the involved joint.71 Hip infection may generate few signs other than pseudoparesis. Prompt drainage of septic hips is necessary because of the risk of developing aseptic necrosis of the femoral head. Long-term dysfunction from gonococcal infection of other joints is an uncommon development.61,72 Although gonococcal sepsis can occur in neonates, the bacteremic phase of disseminated infection usually is clinically silent. Premature infants appear to be more at risk than are term infants for sepsis when bacteremia occurs. Meningitis occurs but is an uncommon finding in neonates with localized or disseminated disease.61,73 Still, when localized or systemic gonococcal infection is suspected or proved in neonates, evaluation of the cerebrospinal fluid is recommended.

Childhood Gonococcal Disease Beyond the Neonatal Period Genital Tract Infection in Prepubertal Girls Gonococcal vaginitis or vulvovaginitis is the most common form of gonorrhea found in prepubertal girls. The prepubertal anestrogenic vaginal mucosa creates an alkaline environment that is more readily colonized and infected on exposure to N. gonorrhoeae than is that of postpubertal girls. Infection of the endocervix, urethra, paraurethral and Bartholin glands, and upper genital tract rarely occur. Gonococcal vaginitis in prepubertal girls almost always is symptomatic, with vulvar erythema and a profuse purulent vaginal discharge. Dysuria, urinary frequency, vulvar discomfort, and pain while walking are common complaints. Concurrent anorectal and tonsillopharyngeal colonization is a common finding (because sexual abuse usually is the means of infection).59,74,75 Symptoms and signs of vulvovaginitis should resolve promptly within a few days once treatment is initiated. Acute manifestations may persist for a few weeks if the child is not treated. The natural course is for inflammation to subside and the discharge to become scant and seropurulent. Infection may resolve spontaneously but sometimes can persist until the child reaches puberty. Prepubertal vulvovaginitis can be caused by numerous irritative and infectious agents, including pinworms, foreign bodies, group A streptococci, Neisseria meningitidis, Neisseria sicca, and Banhamella. catarrhalis. Vulvovaginitis can mimic

263 urinary tract infection. Pyuria can be seen with gonococcal and other etiologies of vulvovaginitis.76 Ascending infection leading to salpingitis or peritonitis is an uncommon occurrence. Among prepubertal girls with gonorrhea, 10 percent have signs suggestive of peritonitis, including fever, diffuse abdominal pain, leukocytosis, and decreased bowel sounds.77

Genital Tract Infection in Prepubertal Boys Gonococcal infection is seen less frequently in prepubertal boys than in girls, reflecting gender differences in rates of sexual abuse. Urethritis is the primary manifestation of gonococcal infection in boys of all ages beyond the neonatal period. Even in young boys, the disease usually is symptomatic and resembles gonococcal urethritis in the adult male. Dysuria, purulent discharge, or both develop 2 to 7 days after exposure. Fever is an unusual occurrence. Symptoms often are mild enough that a child may not be brought for medical care for weeks. Asymptomatic pyuria is a presentation with which health care providers should be familiar. It may be the only finding in some cases and should raise suspicion of gonococcal or chlamydial infection in boys who may have been sexually abused.59,78

Disseminated Disease As in neonates, gonococcal arthritis is the most common form of disseminated disease in older children, adolescents, and adults. Clinical findings are similar to those of septic arthritis due to other causes. Typically one joint is affected, and associated myositis and tenosynovitis may be prominent. Ankles, knees, wrists, and hands are the sites most commonly affected. Polyarticular involvement occurs but less often than in neonates. Gram stain and synovial fluid cultures often are negative. Empiric coverage for N. gonorrhoeae should be considered when septic arthritis occurs in a child who may have been sexually abused.79 Gonococcemia usually is clinically silent but can cause a syndrome of migratory polyarthralgia, fever, and rash that precedes the onset of arthritis by several days to a week. Blood cultures often are negative when care is sought. Symptoms may resolve after a few days even without treatment. Rare cases can resemble meningococcemia with purpura and fulminant sepsis, and these cases sometimes are fatal.80 Skin lesions are common manifestations of gonococcemia and most often take the form of pustules on an erythematous base (Fig. 4). Petechiae, papules, and hemorrhagic bullae can occur. Lesions usually arise on the extremities and are fewer than 20 in number. The finding of skin lesions associated with septic arthritis also has been called the arthritis-dermatitis syndrome. Low-grade fever occurs commonly, but high fevers with shaking chills may occur. Leukocytosis, pyuria, and elevated liver enzyme tests may be observed. Septic joints usually do not become clinically apparent until the second week of disseminated infection.

Anorectal and Pharyngeal Gonorrhea Gonococcal anorectal infection (proctitis) can be associated with pruritis, tenesmus, purulent discharge, or rectal bleed-

C.R. Woods

264

Figure 4 Skin lesion typical of the arthritis-dermatitis syndrome of disseminated gonococcal infection: necrotic pustule with an erythematous halo. Courtesy of Daniel P.Krowchuk, MD.

ing but frequently is asymptomatic. Rectal infection can arise from penile penetration of the rectum or inoculation from vaginal secretions. Approximately 40 percent of girls with genital gonococcal infection will have positive cultures of anorectal specimens. Rectal infection is an unusual occurrence in boys in the absence of rectal intercourse.79,81 Pharyngeal gonococcal infection in all age groups beyond the neonatal period is acquired by orogenital contact. In sexually abused children, the pharynx may be the only site of infection. Gonococcal pharyngitis may be asymptomatic or present as an exudative tonsillopharyngitis that mimics group A streptococcal or viral infections. Cervical adenopathy occurs in some cases. Throat cultures for N. gonorrhoeae should be considered in children with disseminated disease in whom other sites of initial infection are not readily apparent and in those who may have been sexually abused. The pharynx may be the only culture-positive site in some cases of disseminated gonococcal infection. Pharyngeal infection usually resolves spontaneously within 10 to 12 weeks but should be treated when recognized. Current treatment regimens for genital gonococcal infections generally eradicate gonococci from the pharynx.59

Diagnostic Testing Isolation of N. gonorrhoeae in culture remains the standard for diagnosis of gonococcal infections, but nonculture DNAbased tests have become widely used in recent years. Only culture should be used for rectal or pharyngeal specimens. Serologic tests are of limited clinical utility because of low sensitivity (approximately 70%).82 Because gonococci cannot tolerate drying, inoculating clinical specimens onto appropriate media as soon as possible is important. Transport bottles that contain medium and a CO2-enriched atmosphere should be used if definitive processing of the specimen has to be delayed. Transport bottles should be maintained upright when opened to preserve the CO2 atmosphere. Gonococcal colonies usually are evident on agar plates within 24 to 48 hours after inoculation. Positive culture re-

sults, when confirmed, are never considered to be falsely positive, such that specificity and positive predictive values are 100 percent. Selective media, such as modified ThayerMartin (which contains nystatin, vancomycin, trimethoprim, and colistin), is required for cultures of vaginal, rectal, and pharyngeal specimens to suppress contaminating flora. Selective or nonselective media (chocolate agar) can be used for male urethral cultures with equal sensitivity.83 A positive Gram stain has sensitivity of 90 to 95 percent in urethral specimens in males, but the presence of gram-negative diplococci on Gram stain of clinical specimens does not confirm the diagnosis. Nonpathogenic Neisseria spp. and Neisseria meningitidis are morphologically indistinguishable from gonococci.79 Nonculture tests of gonococcal infections now are widely used in the United States and offer the advantage of using urine samples rather than more invasive swabs in some cases and of permitting evaluation for C. trachomatis with the same specimen. The appropriate uses of culture and nonculture diagnostic tests are outlined in Table 3. Nonamplified DNA–DNA hybridization probe tests (eg, Gen-Probe Pace 2) are based on a single-stranded DNA probe complementary to gonococcal rRNA. Sensitivities range from 89 to 97 percent with specificity of 99 percent.82,84,85 Nucleic acid amplification tests (NAATs) are as sensitive as culture, appear to have specificities of at least 99 percent, and can be used to evaluate first-void urine specimens, which permits screening for gonococcal infections in males and females when genital examinations are impractical. Currently available NAATs use standard polymerase chain reaction (PCR)based assay (AMPLICOR; Roche Diagnostics, F. Hoffman-La Roche Ltd., Basel, Switzerland), transcription-mediated amplification (Gen-Probe), and strand displacement amplification (BDProbeTec ET System; BD, Franklin Lakes, NJ).86-88 Urethral specimens for culture should be obtained via gentle insertion of a swab into the urethra (2-4 cm in males, 1-2 cm in females). The swab is rotated one full revolution and withdrawn. In prepubertal girls, a vaginal introital culture should be obtained by gently swabbing the hymenal opening. Deeper insertion is unnecessary. Exudates emanating from the urethral meatus or vaginal orifice also are sufficient for culture. First-catch urine (the first 15 to 30 mL of voided urine) should be collected when nonculture methods on urine are to be used.89 Urine collection should be delayed at least one hour after the most recent void. For proper pharyngeal specimens, the posterior pharynx, tonsillar areas, and faucial pillars should be swabbed.82

Medicolegal Issues N. meningitidis and other members of the Neisseriaceae family are morphologically and often biochemically similar to N. gonorrhoeae. They also may be isolated from sites such as the vagina, blood, and nasopharynx.90 Accurate identification of Neisseria organisms is essential from any pediatric specimen. Misclassification of nongonococcal species as N. gonorrhoeae may lead to very serious social consequences for children and their families by precipitating concerns regarding sexual abuse. Nonculture

Gonococcal infections in neonates and young children

265

Table 3 Laboratory Testing of Specimens for the Presence of Neisseria gonorrhoeae Initial Testing for Diagnosis of Gonococcal Infections

Testing Method and Specimen Type

Tests for screening women for genitourinary tract infection

1. Culture performed on an endocervical swab specimen.* If transport and storage conditions are not conducive to maintaining the viability of N. gonorrhoeae, nucleic acid amplification test (NAAT) or nucleic acid hybridization test (NAHT) can be performed on endocervical swab specimen.† 2. A NAAT performed on urine.

Tests for screening men for urethral infection

1. Culture performed on an intraurethral swab specimen if collecting such a specimen is acceptable and transport and storage conditions are suitable for culture.†‡ 2. A NAAT or NAHT performed on an intraurethral swab specimen if collecting such a specimen is acceptable. 3. A NAAT performed on urine.

Tests for screening men and women for rectal or pharyngeal infection

Culture performed on rectal or pharyngeal swab specimens.*

Testing for gonococcal ophthalmia (neonatal or childhood) or disseminated infection

Culture performed on conjunctival exudate specimens or blood, synovial fluid, cerebrospinal fluid, or pustula skin lesions using non-selective medium (eg, chocolate agar).

Additional Testing after Positive Screening Test Results

Preferences and Comments

Presumptively positive culture (identification in the laboratory of typical Gram-negative, oxidase-positive diplococci consistent with N. gonorrhoeae)

1. Preferred methods for confirmation of N. gonorrhoeae are (1) acid production from carbohydrates,§ or (2) positive results from the Gen-Probe AccuProbe® or PACE 2® tests. 2. Requiring both methods to be positive ensures a high specificity. 3. If an isolate cannot be conclusively identified as N. gonorrhoeae at a local laboratory, it should be sent to reference laboratory for confirmation (especially in cases of alleged sexual abuse, sexual assault, or rape).

Positive nonculture (eg, NAAT, NAHT) test

1. Culture with confirmation as above is the preferred additional test after a positive nonculture test, if specimen transport and storage conditions are suitable. 2. A competitive probe format might be used after a positive NAHT (probe) test, but this approach theoretically is less likely to detect a false-positive result. 3. A NAAT as an additional test after another NAAT or NAHT has received limited evaluation, and certain NAATs might cross-react with nongonococcal Neisseria spp. 4. Antibody tests that detect gonococcal antigens are not recommended for detection of N. gonorrhoeae.

Modified and compiled from: Centers for Disease Control and Prevention.89 *A selective medium (e.g., modified Thayer Martin) should be used for cultures of specimens from these sites. †Transport cultures with an enriched CO2 can be used in some situations. ‡Selective or non-selective media may be used. §N. gonorrhoeae produces acid reactions with glucose but not maltose, lactose, sucrose, or fructose. The species also does not reduce nitrates or hydrolyze tributyrin.

methods consistently identify more clinical specimens as positive than do standard cultures,87 and whether this indicates greater sensitivity, increased false positivity, or a combination of both has been difficult to determine. Because of this possibility

of false-positive results being obtained with nonculture methods, culture remains the medicolegal standard. The Centers for Disease Control and Prevention (CDC) has defined three levels of diagnosis, based on clinical and labo-

C.R. Woods

266 Table 4 Treatment of Gonococcal Infections in the Neonatal Period Disease Category

Treatment Regimen

Comments

Infants born to mothers with gonococcal infection

Ceftriaxone, 25 to 50 mg/kg, IV or IM, not to exceed 125 mg. (single dose)

Ceftriaxone should be given cautiously to hyperbilirubinemic infants, especially premature infants

OR

Gonococcal ophthalmia neonatorum (GON) or Other focal sites of infection (ie, rectum, pharynx, vagina, and urethra)

Disseminated gonococcal infection (septic arthritis, sepsis, meningitis) or Scalp abscess

Cefotaxime, 100 mg/kg, IV or IM. (single dose) Ceftriaxone, 25 to 50 mg/kg, IV or IM, not to exceed 125 mg. (single dose) OR

Cefotaxime, 100 mg/kg, IV or IM. (single dose) OR

Cefotaxime, 100 mg/kg, IV or IM (single dose)

Ceftriaxone, 25 to 50 mg/kg, IV or IM, once daily for 7 days OR

Cefotaxime, 100 to 150 mg/kg per day, IV or IM, in three divided doses, for 7 days

Infants with GON should receive eye irrigation with saline solution immediately upon recognition and at frequent intervals subsequently until the discharge is eliminated. Topical agents alone are inadequate and unnecessary when recommended systemic antibiotics are given. Some experts prefer to continue parenteral therapy with one of these agents until blood (ⴞCSF) cultures have been negative for 48 to 72 hours. Cefotaxime is preferred for infants with hyperbilirubinemia. If meningitis is present, treatment should be continued for 10 to 14 days, and higher doses may be needed.

Largely compiled from (1) Centers for Disease Control and Prevention8 and (2) American Academy of Pediatrics.65

ratory findings, for medicolegal purposes. These levels are more stringent than case definitions used for public health surveillance. A suggestive diagnosis is defined by the presence of mucopurulent endocervical or urethral exudates and sexual exposure to a person with gonococcal infection. A presumptive diagnosis requires two of three criteria: (1) typical gram-negative intracellular diplococci on Gram stain of urethral exudate from males or endocervical secretions; (2) growth of apparent N. gonorrhoeae from such specimens on culture medium, defined as typical colonial morphology, positive oxidase reaction, and typical gram-negative morphology; and/or (3) detection of N. gonorrhoeae by a nonculture laboratory test. A definitive diagnosis requires (1) isolation of N. gonorrhoeae from clinical specimens by culture, as in criterion 2 for a presumptive diagnosis, and (2) confirmation of identity by biochemical, enzymatic, serologic, or nucleic acid testing.91

Treatment Gonococcal antimicrobial susceptibility patterns are ever changing and can vary widely across and within different geographic regions. Healthcare providers must remain alert for modifications of treatment guidelines for their respective geographic locations. In the United States in 2003, 16.4 percent of gonococcal isolates evaluated by the Gonococcal Isolate Surveillance Project were resistant to penicillin, tetracyclines, or both.7 Spectinomycin resistance currently is a rare occurrence. Ceftriaxone resistance has not been observed, although a few isolates with reduced susceptibility to cefixime were isolated in 2003. Approximately 4 percent of isolates are now resistant to quinolones, an issue that is more

common in other parts of the world. Strains resistant to azithromycin and erythromycin also have been identified in the United States. Treatment recommendations are provided in Table 4 for neonatal gonococcal infections and in Table 5 for those beyond the neonatal period. Prepubertal children who weigh more than 45.4 kg (100 lb) should be treated with the dosage regimens recommended for adolescents and adults. These dosages generally have not been studied in populations of prepubertal children but are likely to be highly effective in most cases.65 Ceftriaxone remains a cornerstone of therapy for treatment of gonococcal infections throughout childhood. Children treated with ceftriaxone generally do not require follow-up cultures. If other treatment regimens are used, follow-up cultures may be indicated. Gonococcal DNA should no longer be detectable in clinical specimens 2 weeks after initiation of successful therapy.92 Oral cefixime has an antimicrobial spectrum similar to that of ceftriaxone and may be considered for uncomplicated gonococcal infections in children beyond the neonatal period, provided that follow-up is assured. Cefixime production was discontinued in 2002 but resumed in generic form in February 2004 (an oral suspension is available).93 Other cephalosporins that are safe and highly effective against uncomplicated gonococcal infections in adults, and likely in children as well, include cefotaxime, ceftizoxime, cefotetan, and cefoxitin. Quinolones generally are not recommended for use in persons younger than 18 years of age but may be considered in selected circumstances in which potential benefits of therapy appear to outweigh the potential risks. Ciprofloxacin, ofloxacin, and levofloxacin are the quinolones

Gonococcal infections in neonates and young children

267

Table 5 Treatment of Gonococcal Infections in Children Beyond the Neonatal Period*†‡

Uncomplicated Gonococcal Infections§ Vulvovaginitis, Endocervicitis, Urethritis, Proctitis, or Pharyngitis

Prepubertal Children Who Weigh <100 lb (45kg)

Prepubertal Children Who Weigh >100 lb (45 kg) (and Adolescents)

Ceftriaxone, 125 mg IM in a single dose

Ceftriaxone, 125 mg IM in a single dose#

OR

OR

Spectinomycin,储 40 mg/kg (maximum, 2 g) IM in a single dose PLUS‡ Azithromycin, 20 mg/kg (maximum, 1 g) in a single dose

Cefixime,¶ 400 mg orally in a single dose OR

Ciprofloxacin,†† 500 mg orally in a single dose# OR

Ofloxacin,†† 400 mg orally in a single dose

OR

Erythromycin, 50 mg/kg per day (maximum, 2 g/d) in 4 divided doses for 7 d

OR

Levofloxacin,†† 250 mg, orally in a single dose PLUS‡ Doxycycline,‡‡ 100 mg orally twice a day for 7 days OR

Conjunctivitis§§ Disseminated Gonococcal Infection¶¶## Arthritis, Sepsis, Arthritisdermatitis syndrome

Ceftriaxone, 50 mg/kg (maximum, 1 g) IM in a single dose

Ceftriaxone, 50 mg/kg per day (maximum, 1 g/d) IV or IM once a day for 7 d †††

Azithromycin, 1 g orally in a single dose Ceftriaxone, 1 g IM in a single dose

Ceftriaxone, 1 g IV or IM given once a day for 7 d ††† OR

Meningitis or Endocarditis

Ceftriaxone, 50 mg/kg per day (maximum, 2 g/d) IV or IM given every 12 h; for meningitis, duration is 10–14 d; for endocarditis, duration is at least 28 days

Cefotaxime, 1 g IV every 8 hours for 7 d ††† Ceftriaxone, 1–2 g IV every 12 h; for meningitis, duration is 10–14 d; for endocarditis, duration is at least 28 d

IV, intraveneously; IM, intramuscularly. *Based on recommendations put forth by (1) Centers for Disease Control and Prevention8 and (2) American Academy of Pediatrics.65 †See text for discussion of treatment options for patients with allergies to recommended regimens. ‡In addition to the recommended treatment for gonococcal infection, therapy for Chlamydia trachomatis is recommended due to the common occurrence of coinfections with these microbes. The macrolide and doxycycline components in the table are for this purpose. §Hospitalization should be considered for children (1) who are unlikely to receive prescribed treatment due to personal or parent/guardian failure to adhere to the regimen or (2) whose to infection has not responded to outpatient therapy. 储Spectinomycin is not recommended for treatment of pharyngeal infections. In persons who cannot take a cephalosporin or a fluoroquinolone, a 5-day oral regimen of trimethoprim-sulfamethoxazole may be given. If spectinomycin must be used for pharyngeal infection, follow-up cultures should be performed. ¶Experience in adults suggests that cefixime can be considered for use in children for uncomplicated gonococcal infections, but there are few data available to confirm its effectiveness for gonococcal infections in children. #Alternative regimens for uncomplicated infections include spectinomycin (2 g IM in a single dose), ceftizoxime, cefotaxime, cefotetan, and cefoxitin. Spectinomycin is not recommended for pharyngitis. ††Fluoroquinolones are contraindicated for women who are pregnant or nursing, and usually for persons younger than 18 years of age (see text). These agents are not recommended currently for gonococcal infections acquired in Asia, the Pacific Islands, Hawaii, and California due to quinolone resistance rates in these areas. ‡‡Doxcycline is not recommended for routine use in children younger than 8 years old. §§Eyes should be lavaged with saline initially and at regular intervals until secretions no longer continue to accumulate. ¶¶Hospitalization is required. For older children and adolescents, parenteral therapy can be discontinued 24 to 48 hours after improvement occurs, and the 7-day course completed with an appropriate oral antimicrobial agent. ##Persons with disseminated gonococcal infections also should receive one of the age-appropriate regimens for treatment of possible C. trachomatis coinfection listed in this table as part of treatment for persons with uncomplicated gonococcal infections. †††Some experts advise a 10- to 14-day course of therapy for gonococcal sepsis or septic arthritis.

most widely used for gonococcal infections. Cure rates with these agents for uncomplicated gonococcal infections in adults exceed 98 percent.

Persons of all ages with gonococcal infection are at high risk for having concurrent chlamydial infection. Therefore, treatment recommendations for gonococcal infections be-

C.R. Woods

268 yond the neonatal period include agents active against both organisms (Table 5). Tests for concomitant C. trachomatis infection, human immunodeficiency virus (HIV) infection, and congenital syphilis should be performed in neonates with gonococcal infections of any site. Maternal serostatus for hepatitis B surface antigen also should be confirmed. The mother and her partner(s) should be evaluated for gonococcal infection (and other sexually transmitted diseases [STDs]) and treated accordingly.65 For children with uncomplicated gonococcal infections who are allergic to cephalosporins and who also are too young to receive a quinolone, spectinomycin (Table 5) can be used. If spectinomycin is not readily available, other agents such as ciprofloxacin may be considered. Doxycycline is an option for children 8 years old and older if the gonococcal isolate is known to be susceptible. Azithromycin also may be an option in some circumstances.

Gonococcal Infection and Sexual Abuse of Children Approximately 10 percent of girls suffer sexual abuse during childhood, and rates in male children appear to be approximately 3 percent.94,95 When gonococcal infection is identified in a prepubertal child, sexual abuse must be considered highly likely—nonsexual transmission should never be assumed without extensive investigation of the social setting of an infected child.65,96 STDs overall are found in only 3 to 20 percent of sexually abused children,76,97,98 such that the absence of STDs does not rule out sexual abuse when other findings suggest it has occurred. In addition to being reported to local public health authorities, gonococcal infections in children must be reported to child protective services to ensure the child is not exposed to further abuse (presuming abuse is the mechanism of infection). In the United States, gonorrhea has been the STD most frequently recognized in abused children. The prevalence and presentations of gonococcal infections among sexually abused children are determined by the type and frequency of sexual contact, the prevalence of the infection among the population in which the abuser resides, and the age of the child.99 Among prepubertal girls who have been sexually abused and have a genital discharge, 9 to 11 percent have been found to have gonococcal infection. No cases of genital gonorrhea without genital discharge have been reported in prepubertal girls.18,74,75 The oropharynx may be the only site of infection in children forced to perform oral sexual acts with an infected abuser, and pharyngeal infection may be asymptomatic. Children with suspected gonococcal infection should have a thorough physical examination by someone familiar with the medicolegal issues of and clinical findings among sexually-abused children. Genital, rectal, and pharyngeal cultures should be obtained. Vaginal cultures are satisfactory in prepubertal females (endocervical cultures should be obtained only after puberty). Other sites should be cultured as clinically indicated. Nonculture methods may be used in con-

junction with (but not in place of) cultures to reduce the chance of obtaining false-negative results (with the caveat of potentially having a false-positive result) and to permit more rapid initiation of treatment if nonculture test results will be received more quickly than those of cultures.99 All children with gonococcal infection from abuse should be evaluated for other STDs, including Chlamydia trachomatis, syphilis, hepatitis B virus, and HIV.65

Prevention and Control of Gonococcal Infections All cases of gonococcal infection must be reported to public health officials. Efforts should be made to evaluate, counsel, and treat all sexual contacts of the adult who is the source of gonococcal infection in a child. When patients with gonococcal infections are hospitalized, standard precautions are recommended. This measure includes infants with GON.65

Vaccine Development Research into development of vaccines for gonococcal infections has been ongoing for more than 30 years with little success to date. Two factors render vaccine development difficult: (1) the rapid antigenic variation of gonococcal surface proteins and (2) the reality that natural genital infection does not induce an immune response sufficient to prevent later reinfection by the same strain. Recent molecular analyses suggest that gonococcal transferrin binding proteins (Tbps) might have potential as vaccine antigens because they are exposed on the microbial surface, are expressed in all strains, and have conserved sequences. However, natural infection generates little systemic or local antibody response to Tbps.56 Combinations of antigens from multiple gonococcal proteins likely hold the most hope for vaccine development.

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