Robin Patel MD
VIRIDANS GROUP STREPTOCOCCI, INCLUDING ABIOTROPHIA DEFECTIVA & ABIOTROPHIA ADJACENS
Essentials of Diagnosis
Detailed studies of the ecology of strains in the oral cavity and oropharynx have been performed. The buccal mucosa and initial dental plaque are associated with S sanguis and S mitis, the dorsum of the tongue with S mitis and S salivarius, mature supragingival plaque with S gordonii, and subgingival plaque with S anginosus. In healthy individuals, adherence of viridans streptococci may provide “colonization resistance” within the oral cavity preventing the establishment of more pathogenic bacteria. Fibronectin, a complex glycoprotein found on the surface of oral epithelial cells, selectively promotes attachment of S salivarius, S mutans, and other gram-positive cocci to oral epithelial cells. If fibronectin is lost, as occurs in chronically ill or hospitalized patients, adherence of gram-negative bacilli to oral epithelial cells is increased, predisposing to the development of invasive gram-negative bacillary infections.
Viridans streptococci are strongly associated with bacterial endocarditis (see Chapter 11). Notably, endocarditis caused by A defectiva and A adjacenscarries a higher mortality rate than that reported for viridans streptococci overall. Relapse is reported more frequently in endocarditis cases caused by A defectiva and A adjacens. In endocarditis cases caused by other viridans streptococci, members of the S milleri group are associated with deep-seated abscesses in visceral organs.
Viridans streptococci can be distinguished by their biochemical characteristics. S milleri, S constellatus, and S anginosus constitute the S milleri group of viridans streptococci. Members of the S milleri group of viridans streptococci often require CO2 for growth and typically grow as tiny colonies that may be α, β, or γ hemolytic on sheep blood agar. Members of the S intermedius group often exhibit Lancefield antigens A, C, F, or G and often have a butterscotchlike odor.
A defectiva and A adjacens are defined by their requirement for pyridoxal or thiol group supplementation for growth. These organisms form satellite colonies around Staphylococcus aureus and other microbes, and their colonies are typically small.
Viridans streptococci have a strong association with bacterial endocarditis (see Chapter 11) (Box 50-1). A defectiva and A adjacens were once an important cause of culture-negative endocarditis. However, current laboratory media and techniques enable these “nutritionally variant streptococci” to be identified more readily.
Viridans streptococci account for 2.6% of positive blood cultures reported from clinical laboratories; however, of these, only about one-fifth are thought to be clinically significant (the remainder are attributed to contamination or transient bacteremia). Viridans streptococci are, however, one of the leading causes of bacteremia in febrile neutropenic patients. Viridans streptococcal bacteremia in neutropenic patients usually occurs in association with aggressive cytoreductive therapy for acute leukemia or allogeneic bone marrow transplantation. The prophylactic administration of trimethoprim-sulfamethoxazole or the quinolones, the presence of mucositis, and the presence of indwelling central venous catheters are associated with viridans streptococcal bacteremia in these populations.
BOX 50-1 Major Gram-Positive Cocci Infections
Patients may present with fever alone; however, neurologic, pulmonary, and cardiovascular manifestations may be seen, and a fulminant shock syndrome characterized by hypotension, rash, palmar desquamation, and the adult respiratory distress syndrome may be present. Notably, clinically apparent endocarditis is seldom present in neutropenic patients with viridans streptococcal bacteremia.
Bacteremia associated with S milleri group isolates is often associated with deep-seated abscesses in visceral organs.
When viridans streptococci are recovered from cerebrospinal fluid, they are most often contaminants. Viridans streptococci, however, are rare causes of meningitis, which may occur in patients of all ages, including neonates. Clinical manifestations are typical of acute pyogenic meningitis with evidence of meningeal irritation, neurologic deficits, seizures, and altered sensorium.
Viridans streptococci may be associated with a variety of other infections, including pneumonia, pericarditis, peritonitis, acute bacterial sialadenitis, orofacial and odontogenic infections, endophthalmitis, otitis media, sinusitis, liver abscesses, pelvic abscesses, subphrenic abscesses, appendicitis, abdominal wound infections, cholangitis, mediastinitis, brain abscesses, subcutaneous abscesses, and cellulitis.
The diagnosis of viridans streptococcal infection is made by isolating viridans streptococci from typically sterile sites. As mentioned above, communityacquired viridans streptococcal bacteremias are strongly associated with bacterial endocarditis. This diagnosis may be further confirmed by the presence of clinical findings consistent with endocarditis as well as by the use of echocardiography. A defectiva and A adjacens require pyridoxal or thiol group supplementation for growth. There is sufficient pyridoxal in human blood to support the growth of A defectiva and A adjacens in most blood culture media (with the notable exception of unsupplemented tryptic soy broth). For subculture, however, solid media must be supplemented with 0.001% pyridoxal or 0.01% L-cysteine to sustain growth. As an alternative, the culture plate may be cross-streaked with Staphylococcus aureus to provide these factors and permit the growth of the streptococci as satellite colonies. In addition, as noted above, members of the S milleri group are associated with deep-seated abscesses in visceral organs. Therefore infections caused by these organisms should alert the clinician to initiate an appropriate investigation for the detection of a possible subclinical focus of infection.
Viridans streptococci with a minimum inhibitory concentration (MIC) of ≤0.12 µg/mL to penicillin are defined as penicillin susceptible. Those with a penicillin MIC of 0.25 to 2.0 µg/mL are intermediately susceptible to penicillin. Those with a penicillin MIC of > 2 µg/mL are resistant to penicillin. A high frequency of penicillin-resistant viridans streptococcal infections may be noted in febrile neutropenic patients. For serious infections, such as endocarditis, with these resistant or intermediately susceptible organisms, combination therapy consisting of a penicillin plus an aminoglycoside is recommended. Viridans streptococci are usually resistant to aminoglycosides when traditional breakpoint concentrations for these agents are applied. However, in vitro studies in experimental models of endocarditis have demonstrated synergistic bactericidal activity between combinations of penicillin and aminoglycosides.
Many other β-lactam antibiotics have in vitro activity similar to penicillin against streptococci. In particular, ceftriaxone is an alternative agent to penicillin for the outpatient treatment of viridans streptococcal endocarditis. Other agents with consistently good in vitro activity against viridans streptococci are cefazolin, vancomycin, and imipenem. A defectiva and A adjacens are less susceptible in vitro to penicillin than are most other streptococci. It is recommended that all patients with A defectiva and A adjacens endocarditis be treated with combination therapy consisting of a penicillin plus an aminoglycoside.
Prevention & Control
Endocarditis prophylaxis, as discussed in Chapter 11 on bacterial endocarditis, is used to prevent viridans group streptococcal endocarditis.
GROUP B STREPTOCOCCUS (S AGALACTIAE)
Essentials of Diagnosis
Group B streptococci colonize the mucous membrane of newborns via vertical transmission of the organism from the mother. This takes place either in utero via the ascending route or at the time of delivery. The rate of vertical transmission to neonates born to women colonized with group B streptococci at the time of delivery ranges from 20% to 72%. A high genital inoculum at the time of delivery is associated with a higher rate of vertical transmission. In addition, infants born to heavily colonized women are more likely to develop invasive early onset group B streptococcal disease. Heavily colonized infants have significantly increased rates of early and late onset group B streptococcal disease. Nosocomial transmission of group B streptococci may occur and may be influenced by poor hand washing by health care providers and by crowding.
Several factors have been identified that increase the incidence of invasive early onset infection among neonates born to colonized mothers. They include rupture of the membranes > 18 h before delivery; multiple births; premature rupture of the membranes (< 37-week gestation); maternal fever or amnionitis, or both; black race; age < 20 years; history of previous miscarriage; and preterm delivery.
Group B streptococci may be isolated from genital or lower gastrointestinal tract specimens or both of 5–40% of pregnant women. Lower socioeconomic status, having < three pregnancies, the presence of an intrauterine device, sexual activity, age of < 20 years, and the first half of the menstrual cycle are associated with an increased rate of detection of group B streptococcal colonization in the female genital tract, whereas being of Mexican-American heritage is associated with a decreased rate. Group B streptococci may be harbored in the urinary tract during pregnancy in association with asymptomatic bacteriuria; bacteriuria is a marker for high inoculum in the genital tract.
Group B streptococci are associated with postpartum febrile morbidity with or without bacteremia. In addition, adults with diabetes mellitus, chronic hepatic dysfunction, HIV infection, or malignancies requiring immunosuppressive therapy are also susceptible to group B streptococcal infections.
In addition to host factors, bacterial virulence factors contribute to the host-parasite interaction that determines the outcome between exposure and the development of asymptomatic group B streptococcal colonization or symptomatic group B streptococcal infection. Specifically, a high quantity of cell-associated sialic acid, and its elaboration in supernatant fluid at high concentrations, is associated with virulence. The unique capsular structures of group B streptococci might also enhance the invasiveness of one serotype over another.
Early-onset group B streptococcal neonatal infection has three major clinical expressions: bacteremia with no identifiable focus of infection, pneumonia, and meningitis (Box 50-1). Signs and symptoms of early-onset group B streptococcal neonatal infection include lethargy, poor feeding, jaundice, abnormal temperature, grunting respirations, pallor, and hypotension.
In most infants with pneumonia, symptoms of respiratory distress are present at or within a few hours after birth. Signs of respiratory distress associated with pneumonia include apnea, grunting, tachypnea, and cyanosis. The radiographic findings in infants with pneumonia may be indistinguishable from those of hyaline membrane disease.
Infants with meningitis have a clinical presentation that initially cannot be distinguished from that of infants without meningeal invasion. Lumbar puncture is required to identify neonates with meningitis.
The mortality of early-onset group B streptococcal infection is 10–15% but may be higher in infants with lower birth weights. One-half of patients with meningitis develop seizures within 24 hours of onset; if seizures persist, a poor outcome may follow.
The mean age of onset of late-onset group B streptococcal neonatal infection is 24 days. Bacteremia with concomitant meningitis is a frequent presentation. Signs and symptoms include poor feeding, irritability, and fever. Some infants present with fulminant infection characterized by progression within a few hours from the absence of symptoms to a morbid state with septic shock and seizures with cerebrospinal fluid Gram stains demonstrating sheets of organisms. This fulminant presentation is associated with an increased risk for mortality or permanent neurologic sequelae. Neutropenia on admission, prolonged seizures, and high concentrations of polysaccharide antigen in admission cerebrospinal fluid specimens are also associated with fatal outcomes or permanent neurologic sequelae.
Of all survivors of early- or late-onset group B streptococcal meningitis, 25% to 50% will have permanent neurologic sequelae. One-third of patients with these complications will have severe blindness, deafness, and/or global developmental delay. In the remainder of patients, the deficits are subtler and may be detectable only when language and cognitive function are adequately tested.
Bacteremia without an apparent focus and bone and joint infections are other clinical presentations of late onset group B streptococcal disease. Infants with bacteremia should be evaluated for foci of infection including cellulitis, adenitis, otitis media, conjunctivitis, peritonitis, endocarditis, or deep abscesses. Group B streptococcal osteomyelitis is characterized by an indolent onset in which diminished movement of the involved extremity is the most common symptom. Septic arthritis is associated with an acute onset of symptoms usually in the context of bacteremia. Fever is uncommon in both bone and joint infections. Lower extremity involvement is most commonly observed in patients with septic arthritis, whereas osteomyelitis has a predilection for involvement of the proximal humerus. However, involvement of the femur, tibia, and flat and small bones may be seen.
Group B streptococci cause symptoms of endometritis including fever, malaise, and moderate uterine tenderness. Pelvic abscesses, septic shock, and septic thrombophlebitis are rarely seen. Group B streptococci also cause peripartum bacteriuria that may be asymptomatic or may be diagnosed in association with cystitis or, less frequently, pyelonephritis.
This may occur in patients with diabetes mellitus or neurologic disease. Chest radiographs may demonstrate bilateral or lobar infiltrates. Infection is frequently polymicrobial, although group B streptococci are usually the predominant organisms. Empyema may be present.
Endocarditis caused by group B streptococci is rare. The mitral valve is more frequently involved than the aortic valve, and tricuspid valve involvement is found mainly in intravenous drug users. Underlying heart disease is present in more than one-half of cases, and rheumatic heart disease is the most common underlying condition. Valvular disease, atherosclerotic heart disease, and mitral valve prolapse have also been described as predisposing factors. Large friable vegetations are a frequent feature of group B streptococcal endocarditis. Embolization may occur early. Rapid valvular destruction may occur necessitating early valve replacement in some patients.
This is typically monoarticular and most commonly affects the knee, hip, or shoulder joints (see Chapter 14). Diabetes mellitus is a predisposing factor, as are osteoarthritis and the presence of a prosthetic joint. The most common presenting signs are fever and joint pain in a patient with septicemia. Osteomyelitis may occur as a consequence of adjacent arthritis, peripheral vascular disease, orthopedic surgery, or concomitant infections such as frontal sinusitis. Hematogenously acquired osteomyelitis is most likely to involve the vertebrae. Osteomyelitis may complicate foot ulcers in adults with long-standing diabetes mellitus. In patients with prosthetic joints, group B streptococci typically cause acute onset septic arthritis with local pain, erythema, and swelling.
Group B streptococci may cause cellulitis, foot ulcers, abscesses, and infection of decubitus ulcers (see Chapter 13).
Meningitis, keratitis, endophthalmitis, urinary tract infections in nonobstetric populations, and other unusual presentations may also occur.
The diagnosis of group B streptococcal infection is made by the isolation of the organism from typically sterile sites (eg, blood, cerebrospinal fluid, abscess material). Antigen detection methods may be used to permit a presumptive diagnosis, especially in neonates. Countercurrent immunoelectrophoresis, latex agglutination, staphylococcal coagglutination, and enzyme immunoassays may be used to detect group B streptococcal antigen in various body fluids. A number of selective media enhance the accurate detection by culture of low numbers of group B streptococci from sites such as the genital or gastrointestinal tract of pregnant women. These media usually contain Todd-Hewitt broth with or without sheep red blood cells and antimicrobial agents such as nalidixic acid and gentamicin or colistin. Molecular and antigen detection methods can also be used to detect group B streptococcal genital or gastrointestinal tract colonization in pregnant women.
Group B streptococci are uniformly susceptible to penicillin, although less so than S pyogenes. Penicillin G is therefore the drug of choice; however, because of the increased penicillin MIC (as compared with S pyogenes), the combination of penicillin plus an aminoglycoside is recommended for the treatment of group B streptococcal endocarditis (Box 50-2). Penicillin plus an aminoglycoside exhibit in vitro and in vivo synergistic killing of the organism. Group B streptococci are also susceptible to ampicillin, imipenem, vancomycin, and first-, second- (excluding cefoxitin), and third-generation cephalosporins, although degrees of activity vary. Some isolates are resistant to clindamycin, erythromycin, and clarithromycin; tetracycline resistance is frequently seen. Group B streptococci are uniformly resistant to nalidixic acid, trimethoprim-sulfamethoxazole, and aminoglycosides.
Parenteral therapy of a 10-day duration is recommended for treatment of bacteremia, pneumonia, pyelonephritis, and soft tissue infections, whereas a 14-day minimum duration is recommended for treatment of meningitis and a 4-week minimum for treatment of endocarditis or ventriculitis. In adults with endocarditis, cardiac surgery early in the course may be necessary because of rapid left-sided valvular destruction. In practice, many neonates are empirically treated with ampicillin plus gentamicin.
Prevention & Control
Prevention of early onset neonatal sepsis and postpartum maternal febrile morbidity may be achieved by administration of intravenous ampicillin or penicillin during labor. Women colonized with group B streptococci may be identified by obtaining cultures using lower vaginal and anorectal swabs processed in selective broth media or by using rapid antigen or molecular detection methods when patients are admitted to the hospital. The American College of Obstetrics and Gynecology, the American Academy of Pediatrics, and the Centers for Disease Control and Prevention have developed two strategies (a screening approach and a nonscreening approach) for preventing perinatal group B streptococcal disease (Box 50-3).
To prevent early onset sepsis, maternal chemoprophylaxis should be initiated at least 4 h before delivery and at high doses (see Box 50-3). This allows time to achieve sufficient concentrations of ampicillin or penicillin in the fetal circulation and in the amniotic fluid. Management of neonates born to women receiving chemoprophylaxis should be based on clinical findings.
STREPTOCOCCUS DYSGALACTIAE SUBSPP. EQUISILIMIS & STREPTOCOCCUS ZOOEPIDEMICUS
Essentials of Diagnosis
BOX 50-2 Treatment of Other Gram-Positive Cocci Infections 1,2
The symptoms of pharyngitis caused by these organisms mimic those of S pyogenes pharyngitis (Box 50-1; see also Chapter 48). Poststreptococcal glomerulonephritis has been described following S dysgalactiae subspp. equisimilis and S zooepidemicus pharyngitis. Notably, however, no antistreptolysin O antibody response will be detected as these organisms do not produce streptolysin O. S dysgalactiae subspp. equisimilis pharyngitis has been associated with sterile reactive arthritis. Acute rheumatic fever, however, has not been described in association with S dysgalactiae subspp. equisimilis and S zooepidemicus pharyngitis.
Cellulitis, wound infections, pyoderma, erysipelas, impetigo, and cutaneous ulcers can be caused by these organisms (see Chapter 13). Breaches in skin integrity may provide a portal of entry leading to bacteremia. S dysgalactiae subspp. equisimilis and S zooepidemicus have been isolated in patients with cellulitis after vein harvest for coronary artery bypass grafting and in patients with conditions associated with abnormal venous or lymphatic drainage. Lymphangitis may accompany cellulitis. Bacteremia often occurs as a complication of skin and soft tissue infections.
The skin is the presumed portal of entry in many patients (see Chapter 14). Almost any joint may be involved and frequently the arthritis is polyarticular. Prosthetic joint infection may occur. There have been isolated case reports of S dysgalactiae subspp. equisimilis and S zooepidemicus osteomyelitis.
BOX 50-3 Prevention and Control of Perinatal Group B Streptococcal Disease
S dysgalactiae subspp. equisimilis and S zooepidemicus may rarely cause pneumonia or sinusitis. Infective endocarditis caused by S dysgalactiae subspp. equisimilis and S zooepidemicus is uncommon. Patients may present acutely or subacutely. Destruction of valve leaflets, myocardial abscesses, conduction abnormalities, and severe congestive heart failure may be seen. Major systemic emboli to the spleen, kidneys, myocardium, and central nervous system may occur. Rare reports of S dysgalactiae subspp. equisimilis and S zooepidemicus meningitis exist. These organisms have been associated with puerperal sepsis and endometritis. Neonatal sepsis with S dysgalactiae subspp. equisimilis and S zooepidemicus occurs in premature or low birth weight infants and in the setting of premature rupture of the membranes. The onset of disease is typically within the first week of life.
Bacteremia may occur in S dysgalactiae subspp. equisimilis and S zooepidemicus infections. Other infections caused by S dysgalactiae subspp. equisimilis and S zooepidemicus include pericarditis, pyomyositis, brain abscess, epiglottitis, cervical lymphadenitis, intra-abdominal infection, subdural empyema, arterial-venous fistula infection, peritonitis in dialysis patients, panophthalmitis, and spinal epidural abscess. A toxic shocklike syndrome has also been reported.
The diagnosis of S dysgalactiae subspp. equisimilis and S zooepidemicus infection is made by isolating these organisms from typically sterile sites.
The antimicrobial agent of choice for S dysgalactiae subspp. equisimilis and S zooepidemicus is penicillin G. Other agents with good in vitro activity include cefazolin, vancomycin, the semisynthetic penicillins, and cefotaxime (Box 50-2). The addition of gentamicin to penicillin, cefotaxime, or vancomycin may result in a better outcome in cases of serious infection such as bacterial endocarditis caused by S dysgalactiae subspp. equisimilis and S zooepidemicus.
Essentials of Diagnosis
S bovis causes bacteremia, endocarditis, urinary tract infection, meningitis, and neonatal sepsis (Box 50-1). The gastrointestinal tract is the usual portal of entry in cases of S bovis bacteremia although the hepatobiliary tree, urinary tract, and even dental procedures have been implicated as possible sources.
Isolation of S bovis from typically sterile sites permits the clinical diagnosis of infection.
S bovis is very susceptible to penicillin (MICs range from 0.01 to 0.12 µg/mL) (Box 50-2). Other effective agents include ampicillin, the antipseudomonal penicillins, ceftriaxone, erythromycin, clindamycin, and vancomycin. Penicillin alone given for 4 weeks is adequate to treat patients with S bovis endocarditis. Vancomycin is a reasonable alternative in penicillin-allergic patients. Bacterial endocarditis prophylaxis regimens are given in Chapter 11 and are relevant to S bovis endocarditis.
OTHER GRAM-POSITIVE COCCI
The following organisms are too rare to merit extensive discussion of clinical syndromes, diagnosis, and treatment (see Box 50-4).
S iniae has recently been described as a cause of cellulitis, bacteremia, endocarditis, meningitis, and septic arthritis associated with the preparation of the aquacultured fresh fish tilapia.
Leuconostoc spp. are gram-positive cocci or coccobacilli that grow in pairs and chains; Leuconostoc spp. may be morphologically mistaken for streptococci. They are vancomycin-resistant facultative anaerobes that are commonly found on plants and vegetables and less commonly in dairy products and wine. Leuconostoc spp. have been documented to cause bacteremias, intravenous line sepsis with localized exit site infection and/or bacteremia, meningitis, and dental abscess. Many patients with Leuconostoc spp. infection are severely ill, immunocompromised, or both.
BOX 50-4 Rare Gram-Positive Cocci Infections
Despite exhibiting resistance to vancomycin, Leuconostoc spp. are susceptible to most other agents with activity against streptococci, including penicillin, ampicillin, clindamycin, minocycline, erythromycin, tobramycin, and gentamicin. Some clinical data suggest that penicillin or ampicillin are the agents of choice for treating infections due to Leuconostoc spp.
Pediococcus spp. are also vancomycin-resistant gram-positive cocci. They may be isolated from blood cultures, typically in immunocompromised patients.
Stomatococcus mucilaginosus is a gram-positive coccus that may cause endocarditis, bacteremia, intravascular catheter infection, meningitis, and peritonitis. Many patients infected with S mucilaginosus have underlying serious diseases, neutropenia, the presence of foreign bodies, cardiac valvular disease, and/or a history of intravenous drug use. Destruction of the oral mucous membranes because of chemotherapy or radiotherapy has been hypothesized to play a role in the dissemination of stomatococci from their normal habitat in the oral cavity. Resistance to penicillin has been documented among some S mucilaginosusstrains, and susceptibility to other commonly used antimicrobials varies with the isolate. Stomatococci are uniformly susceptible to vancomycin.
Although aerococci may appear as contaminants in clinical cultures, occasional reports of a clinically significant role of these organisms in cases of endocarditis, bacteremia, and urinary tract infection have been noted. Aerococci are susceptible to penicillin and vancomycin.
Gemella haemolysans has been isolated (as a pathogen) in cases of endocarditis, meningitis, and prosthetic joint infections. G morbillorum has been isolated from blood, respiratory, genitourinary, wound, and abscess cultures and from an infection of an arterial-venous shunt. Gemella spp. appear to be susceptible to penicillin and vancomycin.
Alloiococci have been isolated from the middle ear fluid of children with chronic otitis media and a role for these organisms in the pathogenesis of persistent otitis media has been suggested.
Micrococci are frequently contaminants in clinical cultures but may occasionally cause infections such as infective endocarditis. A review of micrococcal endocarditis in cardiac surgery patients noted that MICs of penicillin ranged from 3.12 to 40.0 µg/mL and those of vancomycin spanned from 1.56 to 10.0 µg/mL. All of the isolates tested were susceptible to cephalothin.
Lactococcus spp. may be associated with bacterial endocarditis. Lactococci are susceptible to vancomycin and moderately susceptible to penicillin.
Globicatella sanguis, the sole species in this genus, has been isolated from patients with bacteremia, urinary tract infection, and meningitis.
Helcococcus kunzii, the only member of this newly described genus, has been isolated from wound cultures, notably those from foot ulcers, characteristically as part of a mixture of bacteria. The clinical significance of this organism is not yet defined.
Centers for Disease Control: Decreasing incidence of perinatal group B streptococcal disease—United States, 1993–1995. 1997; 46(21):473–477.
Centers for Disease Control: Prevention of perinatal group B streptococcal disease: a public health perspective. Morbid Mortal Wkly Rep 1996;45(RR-7):1–24.
Committee on Infectious Diseases/Committee on Fetus and Newborn: Revised guidelines for prevention of early-onset group B streptococcal (GBS) infection. Pediatrics 1997;99:489–496.
Committee on Obstetric Practice, American College of Obstetricians and Gynecologists: Prevention of early-onset group B streptococcal disease in newborns, Comm Opin 173, American College of Obstetricians and Gynecologists, 1996.