CHAPTER 34

Streptococcal

Barry M. Gray

1. Introduction coccus is now a separate genus but will be considered an honorary streptococcus in this chapter because of its sim• The streptococci are a large heterogeneous group of gram• ilarities to enteric streptococci. The enterococcus is part of positive spherically shaped bacteria found widely distrib• the normal bowel flora and has been increasingly isolated uted in nature. They include some of the most important as an opportunistic invader, especially in nosocomial in• agents of human disease, as well as members of the fections (see Chapter 25). This chapter will focus mainly normal human flora. Some streptococci have been associ• on group A and B streptococci and will include current ated mainly with disease in animals, while others have information on pneumococci and other streptococci asso• been domesticated and used for the culture of buttermilk, ciated with human disease. Further details on S. pneu• yogurt, and certain cheeses. Those known to cause human moniae may be found in Chapter 28. disease can be thought of as comprising two broad catego• ries: First are the pyogenic streptococci, including the familiar [3-hemolytic streptococci and the pneumococcus. 2. Historical Background These organisms are not generally part of the normal flora but cause acute, often severe, infections in normal hosts. Streptococcal infections were recognized by Greek Second are the more diverse enteric and oral streptococci, physicians by the 3rd century B.C. A description of which are nearly always part of the normal flora and which erysipelas is recorded in Epidemicus and attributed to are more frequently associated with opportunistic infec• Hippocrates. In the Middle Ages, scarlet fever, or "scar• tions. latina," as it was called in Italy, was an eye-catching and Measured in terms of mortality, morbidity, and eco• notable disease. Sydenham's description in 1676 clearly nomic costs, five streptococcal species are of major im• differentiated this disease from measles and other rashes, portance in human disease. (1) The group A streptococcus, but it was not until 1924 that G.F. and G.H. Dick showed Streptococcus pyogenes, produces a wide range of infec• conclusively that streptococci were the causative agents. tions, from pharyngitis and impetigo to puerperal sepsis Until the advent of penicillin, childbed fever, or puerperal and erysipelas. Their non suppurative sequelae include sepsis, remained one of the most frequent causes of death acute rheumatic fever and acute glomerulonephritis. among otherwise healthy young women. The classic (2) The group B streptococcus, S. agalactiae, is currently works of Holmes, in 1858, and Semmelweis, in 1861, a leading cause of sepsis in newborn infants and a frequent described the transmission of this disease and provided cause of in mothers. (3) The pneu• guidelines for effective preventive measures that are still mococcus, S. pneumoniae, remains the most frequent applicable today. Rheumatic fever was first described by cause of bacterial pneumonia in all age groups and is a Wells in 1812, and Bouillaud described the association of common agent in otitis media, bacteremia, and men• acute rheumatism and heart disease in 1835. In 1836, ingitis. (4) Among the oral streptococci, S. mutans is Bright published his account of "renal disease accom• important as a principal agent of dental caries. (5) Entero- panied with secretion of albuminous urine."(l) Osler pro• vided detailed descriptions of "malignant scarlet fever," Barry M. Gray • Division of Medical Education, Spartanburg Re• which remained common until the advent of antibiotics gional Medical Center, Spartanburg, South Carolina 29303. (see Fig. 1). Severe invasive disease, including necrotizing 673 A. S. Evans et al. (eds.), Bacterial Infections of Humans © Springer Science+Business Media New York 1998 674 Part II • Acute Bacterial Infections

7000 14 c 0 :;::: 6000 !! Scarlet Fever - Number of Deaths 12 ::s .- Q. II) l 0 .c 5000 i a.. (IJ '\ \ 10 -Q) !i 0 C :: 0 '\ 0 4000 .... \ 0 .... 0 - , 8 0,.. "- Q) V \ ... .c 3000 \ Q) E :: 6 Q. ::s \ Z Q) 2000 \ ...4~ 4 (IJ Streptococcal Sore Throat ~- VI Nurrber of Deaths .c 1000 2 (IJ 50"'" F,,,,,,- -Q) D'~h R~'~ C

III' ·...... t 0 ...... 0 1905 1915 1925 1935 1945 1955 1965 1975 Recorded Data 1910-1940 Resident Data 1940-1975

Figure 1. The number of deaths (left-hand scale) from scarlet fever (1900-1960) and from all streptococcal sore throat (1950-1975), with death rates (right-hand scale) per 100,000 population in the United States. Appropriate comparability ratios were applied beginning in 1940, and recorded data compiled according to the geographic locale where the event occurred without regard to residence (1900-1940); resident data were compiled according to the usual place of residence without regard to locale where the event occurred (1940-1975). The population used for determining rates was that of the registration area. Data were not available for streptococcal sore throat for 1900-1950. The number of states reporting for 1900-1905 was 10, gradually increasing to 48 in 1935 and to 50 states in 1960. After 1975, reporting was optional, and no accurate data are available. Sources of data: US Bureau of the Census, Historical Statistics of the United States: Colonial Times to 1970, Bicentennial ed., Part I, p. 77, 1975; National Office of Vital Statistics, Vital Statistics Reports, Vol. 37, No.9 (1920-1950); Centers for Disease Control, Morbidity and Mortality Weekly Report, Annual Supplement, 1960 and 1970. Figure redrawn from Quinn.(l)

fasciitis, "hemolytic streptococcus gangrene," and myo• descriptive value than the term "S. haemolyticus," which sitis, was much less common and did not appear in the was commonly used through the early part of this century. medical literature until the second and third decades of The formal classification of streptococci began when this century. During the mid-1970s to 1980s, cases of acute blood agar came into use and the hemolytic properties of rheumatic fever and acute glomerulonephritis became ex• various organisms were noted. In 1919, Brown used the ceedingly rare (see Fig. 2), and streptococcal disease term "beta" to describe streptococci that produced a 2- to seemed only an inconvenience. By the late 1980s, how• 4-mm zone of clear around colonies grown on ever, rheumatic fever made a dramatic reappearance, blood agar. "Alpha" streptococci were those producing along with an increase in severe invasive infections and incomplete, greenish hemolysis. Most of the isolates from the emergence of a streptococcal toxic shock syn• severe human disease were f3-hemolytic. It was not until dromep-4) Group A streptococci made the headline in the 1928, when Lancefield introduced methods of serotyping popular press as "killer strep," the "flesh-eating bacte• streptococci based on immunologic reactions with cellu• ria. " lar components, that groups and types within groups could In the late 19th century, many investigators contrib• be clearly distinguished. The group antigens were eventu• uted to the understanding of streptococci and their relation ally shown to be specific cell wall carbohydrates. The to human disease. By the 1880s many species had been group A streptococci were further differentiated by the M given names such as S. epidemicus, S. erysipelatus, S. and T protein antigens. The f3-hemolytic streptococci scarlatinae, and S. rheumaticus, which reflected different from most human infections proved to be those of group manifestations of streptococcal . The name S. A. Armed with these new epidemiological tools, Lance• pyogenes dates from this period but is probably of less field and Hare(5) investigated cases of puerperal sepsis Chapter 34 • Streptococcal Infections 675

Number of Positive Number of Cases Throat Cultures __ Rheumatic Fever ...... Glomerulonephritis

8000 40

7000 35

6000 30

5000 25

4000 20

3000 15

2000 10

1000 5 o+-~~-,~~~~~~~~~~~~~~~~~-+o 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 YEAR Figure 2. The number of positive throat cultures (left-hand scale and number of confirmed cases of rheumatic fever and acute glomerulonephritis (right-hand scale) seen in private pediatirc practices participating in streptococcal surveillance studies in Rochester, New York, 1967-1988. The data were kindly provided by Caroline Breese Hall, University of Rochester.

at Queen Charlotte's Hospital in London, beginning in the nized as perinatal for over 20 years. Rather, early 1930s. Of 46 cases of postpartum sepsis, all but one there seems to have been a real increase in group B isolate was group A, and the exception was identified as disease, beginning in the United States and Europe during the prototype of a new serological group, designated the 1960s. By the mid-1970s, numerous reports of group B group G. A year earlier, Hare and Colebrook observed that disease appeared in the literature, and the group B strep• hemolytic streptococci resembling those associated with tococcus was said to have come of age'<6,7) sepsis were never found in vaginal cultures of healthy The pneumococcus has an interesting and important women, but that some women carried streptococci that history, beginning with its association with pneumonia resembled those isolated in bovine mastitis. The latter and later with developments in immunization and serum organisms proved to be members of streptococcus group therapy (see Chapter 28). Studies of the pneumococcus B.(5) have been at the center of major developments in immu• By the late 1930s, the group B streptococci were nology, antibiotics, and, with the discovery of DNA, ge• recognized as important, if occasional, pathogens causing netics and molecular biology. (8,9) postpartum sepsis, amnionitis, endocarditis, and septic The history of S. mutans began in 1924, when Clark abortion. The advent of antibiotics, along with better first isolated the organism from human dental caries. It methods for preventing nosocomial spread, resulted in a was another four decades, however, before Keyes estab• dramatic decline in streptococcal infections on obstetrical lished the "infectious and transmissible nature" of dental services. At Queen Charlotte's Hospital there were very caries in animal models and later in human subjects.(lO,II) few maternal deaths due to either group A or group B Since dental caries are chronic rather than acute infections streptococci from 1940 through the mid-1960s. In this and are not directly life-threatening, the global signifi• same period there were few cases of neonatal sepsis or cance of S. mutans has only recently been appreciated. meningitis attributed to streptococci of any kind in large Dental caries, a complex but diagnosable and treatable series published in the pediatric literature. It appears un• infection, is perhaps the most common bacterial infection likely that group B streptococci went simply unrecog- in humans. 676 Part II • Acute Bacterial Infections

The enterococci, as they were called by Thiercelin in ported on an optional basis, and no reliable data are 1899, were noted as a major aerobic component of feces. available. However, age- and race-adjusted projections of Extremely hardy, they grow in bile, at high or low tem• group B streptococcal disease incidence have been made peratures, in salt, and at high pH. Although for many years from data supplied by four large health departments and grouped with the streptococci because of morphological medical centers in different areas of the United States.<15) similarities, they were transferred to the genus Entero• Several state health departments have instituted reporting coccus in 1984 on the basis of genetic studies. These and of drug-resistant pneumococci. The CDC and the Council several new Enterococcus species were clearly distinct of State and Territorial Epidemiologists (CSTE) have from the "nonenterococcal" group D streptococci, S. recently agreed to make drug-resistant pneumococci noti• bovis and S. equinus. Enterococci have long been known fiable on a nationwide basis, but current data from the as an occasional cause of opportunistic infections, but in CDC are derived from hospital-based surveillance pro• the early 1970s, they began to appear with increasing grams. Vancomycin resistance in enterococci is monitored frequency in reports of , bacteremia, from reports of hospitals participating in the National and pelvic, wound, and surgical infections. They are Nosocomial Infections Surveillance System. Another among the most common organisms causing nosocomial source of data for these and other diseases is the 1992 infections and are difficult to eradicate because of resis• report on "emerging infections" by the Institute of Medi• tance to many antibiotics.(l2,13) cine.(l6)

3.3. Surveys 3. Methodology A considerable number of surveys have been pub• 3.1. Sources of Mortality Data lished on diseases caused by various streptococcal spe• cies. The most informative have been prospective epide• There are few reliable sources of mortality data for miological studies, certain family studies, and surveys of any of the streptococcal diseases. Cause-of-death coding defined populations. These will be reviewed in the de• classifications have been revised about every decade, usu• scription of epidemiological features of specific diseases ally without sufficient details regarding a particular etio• in Section 5.1. logic agent. For example, patients may die of heart failure without rheumatic heart disease being specified; puerperal sepsis may be due to group A or group B streptococci as 3.4. Laboratory Diagnosis well as other organisms; and pneumococcal pneumonia The major streptococcal species associated with hu• deaths are frequently counted with those attributed to man disease are listed in Tables 1 and 2, along with influenza . selected biological and clinical features. Our grouping of species is more for convenience than for taxonomic pur• poses, and various bacteriology textbooks will have dif• 3.2. Sources of Morbidity Data ferent schemes, as well as more detailed information on There are likewise few accurate data on morbidity laboratory methods. The laboratory procedures and the from streptococcal infections. Since 1971, streptococcal particular approach to identification will of course depend sore throat, scarlet fever, and acute rheumatic fever have on whether is for clinical or research purposes been reported only optionally to the Centers for Disease and the degree of specificity required. Control and Prevention (CDC), which now relies primar• 3.4.1. Isolation and Identification. ily on selected hospital and population surveys. Monitor• 3.4.1a. Media and Growth Conditions. Most strep• ing of recent outbreaks of rheumatic fever by the CDC has tococci grow poorly on ordinary nutrient media but grow been incomplete, and no mechanism for systematic na• quite well on media enriched with blood, brain, or heart tionwide reporting has been adopted. The best longitudi• infusion, serum, or glucose. Todd-Hewitt broth is an nal incidence data on rheumatic fever are from Denmark, enriched buffered medium that has become a standard where meticulous records have been kept for over a 100 liquid medium for most streptococci. In the United States, years.(l4) The CDC began a passive nationwide surveil• most laboratories use 5% sheep blood agar, whereas in lance for invasive group A streptococcal infections in Britain horse blood is generally used. Both give good 1993 and expanded to a population-based active surveil• hemolysis, although with sheep blood it may be necessary lance in 1994. Group B streptococcal disease is also re- to "stab" the agar in the area of inoculation to ensure Table 1. The Major Species of Pyogenic Streptococci Causing Disease in Humans

Species Presumptive Definitive Association designation Lancefield group Hemolysis identification identification Ecological niche Normal flora with disease

Group A. S. pyogenes A 13 Bacitracin M proteins Oropharynx No (modest Pharyngitis, streptococci sensi ti vi ty, latex T proteins carrier rates) impetigo, agglutination and Opacity factor erysipelas, other antigen Molecular methods bacteremia detection methods

Group B S. agalactiae B 13 CAMP test positive Capsular Lower bowel, High carrier rate Neonatal sepsis, streptococci polysaccharides genital tract in normal meningitis, c-protein population postpartum DNA fingerprint infections, endocarditis, cellulitis

Group C S. equisimilis C 13 "Not A or B" DNA fingerprint (Swine, humans) Occasional Pharyngitis,

streptococci S. zooepidemicus C 13 Latex agglutination Bacteriophage (Horses, cattle, No bacteremia,

S. equi C 13 other animals) No wound infections, cellulitis, often veterinary-related

Group G "Large colony" G 13 "Not A or B" Some with M-12 Pharynx, bowel Occasional Pharyngitis, streptococci group G Latex agglutination protein cellulitis, bacteremia Pneumococci S. pneumoniae None (has a sensitive, Capsular Nasopharynx High carrier rate Lobar pneumonia, 9 pneumococcal bile soluble polysaccharides in normal otitis media, .@l C-polysaccharide) Surface protein population bacteremia .,!O' Molecular methods meningitis ~

'JJ

~ I ;;--= a

~

="...... 0'\ -.....I Q()

:l~ = i = ~ ::b Table 2. The Major Species of Oral and Enteric Streptococci and Enterococci Causing Disease in Humans [

Lancefield Presumptive Definitive Normal -;-..,= Species name group Hemolysis identification identification Ecological niche flora Association with disease g til Dental/oral and S. mutans None, E None Cell wall carbohydrate Tooth surface, Yes Dental caries, endocarditis "Viridans" DNA hybridization dental plaque streptococci S. sanguis None, H a, [3, none Biochemical Dental plaque Yes Endocarditis, brain S. mitis None, 0, K, M a, [3, none Biochemical Oral cavity Yes abscesses, bacteremia S. salivarius None, K None Biochemical Tongue Yes Bacteremia s. sobrinus (x, none Biochemical Oral cavity Yes Bacteremia S. oralis (x, none Biochemical Oral cavity Yes Bacteremia "Milleri" group Minute colony A, C, F, G, none a, [3, none Biochemical Oral cavity Yes Endocarditis, dental S. anginosis C [3 Biochemical Oral cavity Yes abscesses, brain S. costellatus Biochemical Oral cavity Yes abscesses, liver abscesses S. intermedius Biochemical Oral cavity Yes Nutritionally S. mitis (mutant) Various a, [3, none Require pyridoxal Biochemical Oral cavity Yes Endocarditis deficient S. sanguis Various a, [3, none Require pyridoxal Biochemical Oral cavity Yes Endocarditis streptococci (mutant) S. salivarius Various el, none Require pyridoxal Biochemical Oral cavity Yes Endocarditis (mutant) Microaerophilic Peptostrepococcus Some D None Biochemical Oral cavity, Yes Abscesses, otitis media, and anaerobic (five species) bowel pelvic inflammatory streptococci disease N onenterococcal S. bovis 0 a Biochemical Bowel Yes Bacteremia, endocarditis, group D S. equinus 0 a Biochemical Bowel Yes opportunistic infections Enterococci E. faecalis 0 none, [3 Growth in bile- Biochemical Bowel Yes Urinary tract and surgical (> 15 species) E. faecium 0 a, [3, none esculin 6.5% Biochemical Bowel Yes infections, bacteremia, NaCl endocarditis, wounds, opportunistic infections Chapter 34 • Streptococcal Infections 679 subsurface growth for the action of oxygen-sensitive he• pearance, but group B streptococci are usually larger, molysins. While most streptococci grow well in a normal more mucoid, and have a narrower zone of hemolysis that atmosphere, some species, particularly the "S. milleri" is often less distinct. About 1% of wild group B strains are group and the peptostreptococci, do not show good nonhemolytic, but this depends to some degree on the growth or hemolysis without a reduced oxygen atmo• media used. Streptococci of the "milleri" group have very sphere. Pneumococci prefer to grow in 5% CO2 or in a tiny colonies but usually have comparatively large zones candle jar. Most streptococci grow best at 35 to 37°C, of f3-hemolysis; these include group F and the "minute although the enterococci will also grow at 10 and at 45°C. colony" group A, C, and G streptococci. The a-hemolytic Routine isolation of group A streptococci from throat streptococci are quite heterogeneous and are difficult to cultures is adequately accomplished using plain sheep distinguish even to the practiced eye. The pneumococci, blood agar incubated in air at 37°C; cultures read as however, are usually smooth and glossy with central cra• negative at 18-24 hr should be incubated an additional ters formed by autolysis as the colonies grow beyond 18- 24 hr for optimal sensitivity. Alternatively, throat cul• 24 hr. Colonies of type 3 pneumococci are often very large tures may be incubated anaerobically, although this may and have a distinctive mucoid appearance. Enterococci increase the recovery of non-group-A f3-hemolytic strep• have rather buttery colonies, compared to most of the tococci. Selective media containing trimethoprim-sulfa• streptococci, and usually produce no hemolysis or may be methoxazole have also been evaluated and recommended f3-hemolytic on horse blood and a-hemolytic on sheep for use in throat cultures. (17) blood. Many laboratories now process vaginal or anorectal 3.4.1c. Presumptive Identification. For practical cultures to determine colonization by group B strepto• purposes, group A streptococci can be identified presump• cocci in pregnant women. A selective broth medium is tively by the bacitracin sensitivity test of Maxted in which generally required to minimize overgrowth of other or• a 0.04-unit bacitracin (TAXO) disk is placed on a pure ganisms. We currently use Todd-Hewitt broth containing subculture of a f3-hemolytic streptococcus. Group A nalidixic acid, polymyxin, and crystal violet.(8) A similar streptococci are extremely sensitive and uniformly show a medium is available with colistin plus nalidixic acid but zone of inhibition, whereas only 5-10% of group C or G without crystal violet ("Lim" broth). A broth containing strains may give a false-positive result. The simplest of gentamicin plus nalidixic acid has also been widely used, several tests for group B streptococci is the CAMP test although we found that some group B strains were inhibited (described by Christie, Atkins, and Munch-Petersen in by the gentamicin.(l7,18) A fairly satisfactory commercial 1944). The test is performed by inoculating a streak of the solid medium is Columbia CNA agar, which contains streptococcus perpendicular to a streak of Staphylococcus colistin and nalidixic acid. For isolation of pneumococci aureus on a sheep blood ; an arrowhead-shaped from nasopharyngeal carriers, a selective medium is also area of complete hemolysis indicates the presence of essential; we have favored blood agar containing 4 mgt CAMP factor, which enhances the effect of the staphylo• liter of gentamicin sulfate.(l9) The enterococci grow on coccal f3 lysin. Streptococci reported simply as "not A or nearly all conventional media, including EMB (eosin• B" on the basis of presumptive tests usually prove to be methylene blue) used for gram-negative enteric organisms. group C or G. Pneumococci are distinguished from other 3.4.1h. Colony Morphology and Hemolysis. The a-hemolytic streptococci by sensitivity to optochin in a first step in identifying a streptococcus is examining colo• manner similar to that of the bacitracin test for group A nies grown on blood agar for characteristic morphology streptococci. In addition, the bile solubility test of Neufeld and hemolysis. A , for example, will have remains useful for separating pneumococci from the occa• much extraneous growth, but the bacteriologist will be sional optochin-sensitive viridans streptococcus. Entero• looking for group A streptococci that have small (0.5-1 cocci are identified by growth on bile-esculin media and mm), opaque white colonies surrounded by a wide zone of in 6.5% NaCl. Further identification of these and the clear f3-hemolysis. Stabs made into the medium in the area viridans streptococci is done with various panels of bio• of inoculation will usually clear first because the strepto• chemical tests. lysin 0 is more active in the absence of air. Streptolysin S, 3.4.1d. Rapid Diagnostic Tests. A number of di• which is active on the surface, does not always produce rect antigen detection tests are currently in use for diag• complete hemolysis in young cultures. Occasional strains nosis of streptococcal pharyngitis. Most of these methods produce large (> 1 mm) mucoid colonies, due to the ex• are based on the extraction of cell wall antigens from pression of hyaluronic acid capsules (especially M type 18). throat swabs and their detection by agglutination of latex Groups A, C, and G streptococci are similar in ap- or other particles coated with antibody against the group A 680 Part II • Acute Bacterial Infections

polysaccharide. These "rapid strep tests" yield results in gens vary considerably in their reliability. This is because 10 to 60 min and permit the physician to appropriately reagents are usually made by coating the latex particles treat streptococcal pharyngitis without the delay of con• with antibodies of mUltiple capsular serotypes, thus dilut• ventional cultures. In general, the specificity of these tests ing the sensitivity to anyone antigen; the reagents may is excellent: 90-95%. The sensitivity, however, varies detect some serotypes better than others and some not at from 60 to 85%. Those patients with strong positive all. Gene probe assays, noted below, may eventually pro• cultures are nearly always detected, but up to half of those vide adequately sensitive and reliable direct detection. with "1 +" cultures (one to ten colonies per plate) may go 3.4.le. Definitive Identification. Streptococci are undetected. The clinical significance of this shortcoming classified into Lancefield groups on the basis of their cell is not entirely clear. The latter group may include some wall carbohydrate antigens. The classical methods of patients who are "carriers" and not at risk in terms of the grouping employ an extraction step, usually hot acid acute infection or sequelae. However, 35-45% of those (Lancefield method) or nitrous acid, followed by detec• with false-negative rapid tests (but 1+ positive cultures) tion of liberated antigens with specific rabbit antisera. have evidence of true infection as determined by a rise in More recently, latex and similar particle agglutination kits streptococcal antibody titers. Left untreated, some of make it possible for any laboratory to provide rapid and these patients could be at risk for developing acute rheu• accurate group identification without having to maintain matic fever. For this reason it is recommended that a throat serological supplies. culture be done when the rapid test is negative. Several Typing of group A streptococci is done by precipita• newer methods, including an optical immunoassay and tion of M and T proteins with specific antisera. The T gene probe tests, are claimed to have sufficiently good proteins are trypsin-resistant antigens that are useful as sensitivity to obviate the "back-up" throat culture, but markers for certain M types and for strains having no experts remain cautious, pending further evaluation of detectable M protein. T typing is done by agglutination these products.(20) after trypsinization of the streptococcal cells. M typing, Two problems continue to limit the usefulness of the done by precipitation after an antigen extraction step, is antigen detection tests. One is that they detect only group then done on the basis ofT-typing results. For example, Tl A streptococci, whereas acute pharyngitis is sometimes strains are invariably Ml, and T3 strains are M3, whereas caused by group C or G streptococci, which may also T8/25/Imp.19 strains may be M2, 55, or 57. Over 80 M require antibiotic therapy. The other is cost: A blood agar types have been described, but up to a quarter of isolates plate currently costs about $0.20, whereas latex agglutina• are not typable with either T or M antisera. Because group tion tests cost about $2.00 each, and an optical immuno• A typing is not readily available, the opacity factor neu• assay costs about $5.00. However, federal regulations tralization test described by Fraser and Maxted in 1979 has recently adopted in the Clinical Laboratory Improvement recently been reevaluated and modified by Johnson and Act (CLlA) classify the processing of throat cultures as a Kaplan.(23) This test is relatively simple and correlates "complex" procedure. Many office laboratories face dif• well with M typing. The epidemiological importance of ficulties in complying with the new requirements for group A typing is obvious when it is noted that certain M throat cultures but may nevertheless perform antigen de• types are commonly associated with specific kinds of tection as a "simple" laboratory test. infection or sequelae. Table 3 lists the most common M Similar particle agglutination methodologies have types associated with uncomplicated pharyngitis, severe been employed for detecting group B streptococcal anti• systemic infections, and rheumatic fever,(24) and with gens in cerebrospinal fluid (CSF) or urine. They are quite acute glomerulonephritis. (25) It is of particular interest that reliable in detecting antigen in CSF from infants infected Ml strains are common in both uncomplicated pharyngitis with group B streptococci. Testing of urine samples has and in severe invasive disease, but epidemiological evi• been discouraged because the urine sample may be posi• dence suggests that the serious disease is caused by espe• tive as the result of skin or genitourinary contamination, cially virulent strains or clones of type MI, and that or possibly from intestinal absorption and urinary excre• virulence is not always associated as a general property of tion of antigen. (21) So far, no rapid tests have proved that serotype. (24) Molecular methods, described below, sensitive enough to determine maternal colonization di• have now begun to confirm such observations and shed rectly from vaginal swabs, but detection of "heavy" colo• light on the evolution of virulent clones and the virulence nization by some tests may be sufficient to identify most genes themselves. (26-28) of the patients at risk for invasive disease.(22) The typing of group B streptococci is based on the de• Antigen tests for pneumococcal polysaccharide anti- tection of capsular polysaccharides, as outlined in Table 4. Chapter 34 • Streptococcal Infections 681

Table 3. Group A Streptococcal M Protein Serotypes Commonly Associated with Uncomplicated Pharyngitis, Scarlet Fever, Severe Systemic Infections, Acute Rheumatic Fever, and Acute Glomerulonephritis, Listed in Approximate Order of Frequencya

Severe systemic Acute Uncomplicated pharyngitis Scarlet fever infections rheumatic fever Acute glomerulonephritis

3 3 2 12 4 3 4 1 18 18 49 2 22 12 5 12 28 6 22 4 4 3 2 5 6 55

aData from Johnson et al)24) Coleman et a1)186) and Dillon et at. (25) Severe infections included streptococcal toxic shock, septicemia, pnenumonia or empyema, joint, and deep soft tissue infections, Note that strains associated with acute glomerulonephritis may be isolated from throat (M! and M12) or skin sites (M55) or either throat or skin (M4, M49),

There are four major types: la, Ib, II, and III, and three planted by multilocus enzyme electrophoresis and mo• newly recognized types: IV, V, and VI (formerly known as lecular methods. MJl9), In her original description of the type polysac• The pneumococci are divided into serological types, charides, Lancefield noted that, finding no antigens analo• according to capsular polysaccharides. The Danish typing gous to the M proteins of group A streptococci, she was system currently in use recognizes 48 types, many of looking for capsular materials like those found in the which have several closely related subtypes that corre• capsules of pneumococci, The group B indeed proved to spond to individual types of the American system. The have capsular polysaccharides and are all similar in struc• subtypes are denoted by the Arabic type number plus a ture, composed of glucose, galactose, and N-acety 19lucos• letter to indicate the SUbtype. For example, types 1-5 each amine, Unlike pneumococci, they all have side chains contain only one distinct type; type 6 (usually called containing terminal sialic acid residues that are major "group" 6) includes type 6A (America type 6) and type antigenic determinants,(29) The newly designated type VI 6B (American type 26); type 9 includes four subtypes, of differs from the others by the absence of N-acetylglucos• which only type 9N (American type 9) and 9V (American amine in the capsular polysaccharide, (30) Type Ib strains type 68) are at all common among clinical isolates. and some type II and type III strains also carry the c Knowledge of the distribution of types in human infec• protein, formerly called the "Ibc protein," a complex tions led directly to the selection of the most important antigen, part of which is capable of binding secretory IgA. types in the formulation of pneumococcal vaccines.(31) The R antigen occurs on some type II and III strains, but is The pneumococci can be further delineated within capsu• not seen frequently among human isolates, The X antigen lar types by typing surface protein antigens that occur on is found almost exclusively in veterinary strains, partic• essentially all clinically important isolates.(32) Pneumo• ularly those from bovine mastitis, To distinguish among coccal surface protein (PspA) is highly variable, but sev• strains of the same capsular type, a bacteriophage typing eral variants of the protein are quite common and are scheme has been employed in the past, but is being sup- currently under investigation as potential vaccines. Group D and viridans streptococci are usually speci• ated by their pattern of biochemical reactions.(17) Various test kits and automated equipment are in general use in Table 4. Type-Specific Antigens of Group B Streptococcia most clinical laboratories and give basically similar re• Capsular polysaccharides Ia ib II III IV V VI sults. However, these products do not always conform to c protein + (+) (+) ? the latest taxonomic changes. Two major identification aSerological classification is detennined according to the capsular polysaccharide, schemes are currently in use, one from Great Britain and The c protein was fonnerly called the "Ibc protein" becuase of its association with the other from the CDC in the United States. They differ Ib and Ie strains, Ib strains (which always have this protein) are now designated Ib/ c, and Ie strains (which have the la capsule) are designated laic, About one third of mainly in the classification of group F and the milleri type II strains have the c protein and are noted as II1c; the frequency of c protein in group. "S. milleri" currently consists of three species: S. types IV, V, and VI is not well described. The R antigen occurs occasionally in type II and III strains, but like the X antigen is more common in veterinary than in anginosis, S. constellatus, and S. intermedius, which dif• human isolates. fer in their production of [3-glucosidase, hyaluronidase, 682 Part II • Acute Bacterial Infections

and several other glycosidases. Nutritionally deficient greatly on the selection of primers and the conditions of streptococci causing endocarditis are thought to be mostly the assay. mutant subspecies of S. mitis that require pyridoxal for Several other molecular approaches differentiate growth. (33) S. mutans includes eight serological types among streptococcal strains or types but are not neces• based on cell wall carbohydrates, but epidemiological sarily intended to correlate with given M or T typing studies now favor molecular methods for distinguishing systems. "Ribotyping" is based on the pattern of ampli• strains among types. (10) fied ribosomal RNA in agarose gel electrophoresis. De• Most enterococci share a glycerol teichoic acid anti• pending on the primers utilized, species-specific and gen with the group D streptococci.(34) However, they are sometimes strain-specific identification may be possible. usually characterized by their ability to grow in broth Because ribosomal RNA nucleotide sequences are highly containing 6.5% NaCI and hydrolyze eschulin in the pres• conserved, few differences may be seen even between ence of 40% bile salts (bile-esculin medium). Strains are strains of differing M types.(39.40) Restriction endonucle• divided into 4 major groups and 15 main species using a ase analysis (REA) is a kind of DNA "fingerprinting" panel of biochemical tests. A variety of methods have using endonucleases such as EcoRI or HindIII that cut been tried with only modest success for subdividing the chromosomal DNA into small fragments suitable for sepa• major human pathogens, E. faecalis and E. faecium, but ration with conventional agarose gel electrophoresis'<39.41) molecular methods are beginning to prove useful for in• This method may be a helpful supplement to serotyping, fection control and epidemiologic purposes. especially for nontypable strains, but it is limited by 3.4.1f New Methods of Identification. Molecular technical problems of resolution and comparison of the methods have now been applied to various streptococcal DNA fragments of different strains, making it often too species for direct detection, identification, epidemiology, general for epidemiological applications. An extension of and studies of molecular evolution. Although it is unlikely this method, usually called restriction fragment length that the polymerase chain reaction (PCR) will replace the polymorphism (RFLP), relies on endonucleases, such as blood agar plate anytime soon, hybridization with labeled SmaI or SfiI, that cut DNA at relatively fewer sites, pro• gene probes have been successfully employed for detec• ducing longer, more distinctively sized fragments.(26) tion of group A streptococci from throat swabs of patients These larger (20-500 kb) fragments must be resolve using with pharyngitis. (35) These methods are still cumbersome, pulse field gel electrophoresis (PFGE), because of the time-consuming, and more suited to batch processing, but peculiar dynamics of migration of large pieces of DNA future developments may make them more suitable clini• through agarose gels. Yet another approach uses PCR cal use. Detection of pneumococcal DNA in materials amplification of sections of chromosomal DNA by "arbi• such as blood cultures and middle-ear fluids has also been trary" or "random" primers: These are termed "arbi• demonstrated by PCR, using primers derived from known trarily primed" PCR (AP-PCR) or "random amplified nucleotide sequences from genes coding for autolysin(36) polymorphic DNA" (RAPD).(42) Various methods similar and pneumolysin. (37) to those just described have been employed for epidemio• The molecular equivalent of serotyping of group A logical studies of group B,(43,44) and group G(45) strep• streptococci has been demonstrated for 16 common M tococci, pneumococci, (46.47) and enterococci.<48) protein types by PCR amplification followed by hybrid• Molecular methods have also focused on genes of ization with labeled probes whose DNA sequences are particular interest because of their function in disease, complementary with the N-terminal type-specific portion antibiotic susceptibility, or distribution in nature. Two of the M protein gene.(38) Similar methods could supple• highly pathogenic clones of group A streptococcus were ment or perhaps eventually replace conventional serotyp• tracked and delineated by the allelic variants of their ing for epidemiological purposes. However, the multi• scarlet fever toxin (SPE-A), serotyping, and multilocus plicity ofM protein genes both within and among the >80 enzyme electrophoresis (MLEE).(49) The DNA finger• serotypes presents many of logistical difficulties of sero• prints of penicillin-binding proteins, along with capsular typing as well as some problems peculiar to the new and surface protein typing and MLEE, have been used to technology itself. Many strains have a number of "M study the epidemiology and clonality of antibiotic-resis• proteinlike genes": some may look like M protein genes tant pneumococci,(50) but code for proteins with lectinlike functions, such as Molecular analysis is now beginning to provide clues binding of immunoglobulins or fibronectin, and some to the regulation of genes associated with virulence, such appear to be extra copies or even defective genes. The as those needed for M protein expression(27) and synthesis amplification and/or detection of these genes may depend of hyaluronic acid capsulars.(51) A broader evolutionary Chapter 34 • Streptococcal Infections 683 study of the "virulence gene cluster" of group A strep• modest, is more helpful than a single determination. Test tococci has revealed a relatively small number of distinct kits give a titer of > 166 Todd units as elevated for adults, patterns of the mutigene family containing most of the but there is considerable variation in the "normal" values important genes thought to be associated with virulence. (28) among popUlations and laboratories. In general, single 3.4.2. Serological and Immunologic Diagnostic ASO titers above 250 in adults and above 300 in school• Methods. Antibody tests have been developed as clini• aged children are considered elevated. Compared to phar• cal and epidemiological tools in the study of group A, yngitis, skin infections tend to elicit feeble ASO responses group B, and pneumococcal infections. In general, anti• but greater responses to DNase B. The anti-DNase B titer bodies are markers of past experience with the organisms peaks later, at 6-8 weeks after either skin or throat infec• and do not indicate when an infection took place. For this tions. This test is often useful when the initial ASO is low reason they are most useful when acute and convalescent or negative. There is less clinical experience with the antibody levels are compared in relation to an episode of antihyaluronidase and antistreptokinase tests, although presumed infection. they may give comparable results and may be useful as Assays for the group A streptococcus are based on confirmatory tests. The Streptozyme hemagglutination the development of antibodies either to cellular antigens test (Wampole Laboratories, Stamford, CT) is a crude or to extracellular enzymes. These are listed in Table 5 and screening test based on reactions with an unspecified further described in Section 4. Tests for antibody to M mixture of streptococcal antigens. It is simple and widely proteins, which confer immunity, and to the group A available but is not considered sufficiently reliable by carbohydrate have been used primarily for research pur• many authorities. Positive responses appear earlier (1-2 poses. Assays used clinically for confirmation of recent weeks) and should always be confirmed with one or more infections have been reviewed by Ayoub.(52) The anti• of the standardized assays whenever rheumatic fever or streptolysin 0 (ASO) is the most reliable and is widely acute glomerulonephritis is suspected. (20) available. It is of no immediate value in the diagnosis of Assays for antibody to pneumococcal and group B acute streptococcal pharyngitis, and it should not be ex• streptococcal capsular polysaccharides have employed pected to differentiate carriage from infection. Neverthe• radioimmunoassay (RIA) for total antibody and enzyme• less, about 80% of patients with rheumatic fever or linked immunosorbent assays (ELISA) for total and class• pharyngitis-associated acute glomerulonephritis infection specific antibody determinations. Since both pneumo• will mount a significant ASO response. A rise in titer is cocci and group B streptococci have multiple capsular usually seen 3-6 weeks after infection, and a rise, even if types, antibody to specific types must be considered. AI-

Table 5. Group A Streptococcal Antigens and Antibodiesa

Antibody Clinical interpretation

Cellular antigens M protein (M protein) Type-specific, confers immunity. Some antigens cross-reactive with sarcolemma of heart muscle Group A carbohydrate (Group A CHO) Slow response following infection Hyaluronic acid capsule None Not antigenic Extracellular enzymes Streptolysin 0 Antistreptolysin 0 (ASO) Increases after most group A infections, more reliable for throat than skin infections Deoxyribonuclease A, B, C, D Anti-DNase B Most useful test for skin infections, also reliable for throat infections; anti-DNase A and C inconsistent Hyaluronidase Antihyaluronidase Increases after most group A infections Streptokinase Antistreptokinase (ASK) Increases after most group A infections; streptokinase A more common than B Nicotinamide adenine Anti-NADase (anti-DPNase) Response better after throat than skin infections; common to group A, C, dinucleotidase and G streptococci Proteinase Antiproteinase Antibodies appear in small amounts following infection with group A Erythrogenic toxins A, B, Antierythrogenic toxin Toxin produces rash of scarlet fever; Dick skin test for immunity or and C susceptibility aAdapted from Quinn.ll) 684 Part II • Acute Bacterial Infections

though it has so far proved impossible to establish an listed in Table 3, are the major virulence factors of group absolute or minimal protective antibody level, infection A streptococci, contributing to the organism's resistance appears to be more common in subjects with low antibody to phagocytosis in the absence of type-specific anti• levels against the specific capsular antigen of the type body.(53) M proteins bind host proteins, especially fi• causing infection. Assays for type-specific pneumococcal brinogen, as a ploy to evade host defense mechanisms. antibodies are now commercially available. They are cur• Although immunity appears to be lifelong, most humans rently used in screening selected patients when a gener• are usually infected by only a few different types and alized unresponsiveness to polysaccharide antigens is sus• remain susceptible to the other types. Thus, repeated epi• pected. For this purpose, it is useful to compare antibody sodes of streptococcal infection may be due to different levels before and 4 weeks after administration of pneu• types rather than to a failure of host response. Certain M mococcal vaccine. types, especially MI and M3, have been associated with more severe forms of disease. (4,24) The existence of "rheu• matogenic" types or strains has been debated for many 4. Biological Characteristics of the Organisms years. Although "rheumatogenicity" is not determined by M type alone, evidence for the cross-reactivity of certain The various streptococcal species have many biolog• M proteins with heart and brain tissue now strongly sug• ical similarities and differences. The genus name suggests gests autoimmune mechanisms for the etiology of acute a "twisted chain," which describes the microscopic ap• rheumatic fever and Sydenham's chorea.(54-56) pearance of many species, especially when grown in broth The group A cell wall carbohydrate is a polymer of culture. The pneumococci are commonly described (and rhamnose withN-acetylglucosamine side chains. Humans were formerly named) as diplococci because of their pro• normally make antibodies to this antigen, but antibodies pensity to occur in pairs, but they are often indistinguish• play no role in protection. There is now evidence that this able from other streptococci in blood cultures. All the antigen may playa role in sequelae of streptococcal infec• streptococci have a tough cell wall composed of cross• tions by inducing antibodies cross-reactive with cyto• linked peptidoglycans. Most have a polysaccharide group keratin. (57) This could provide an explanation for the joint antigen associated with the cell wall, and some have and skin manifestation of acute rheumatic fever and of teichoic acids as major or additional components. Pneu• guttate psoriasis. mococci exhibit prototypic bacterial polysaccharide cap• Hyaluronic acid capsules are also produced by some sules. The group A streptococci, in contrast, have the M (especially M18) strains, giving colonies a large, highly proteins on their exterior surface, but these appear to play mucoid appearance. This capsule material is indistin• a similar role in helping the organisms resist phagocytosis. guishable from the ground substance of mammalian con• The group B streptococci, like pneumococci, have poly• nective tissue and is not immunogenic. Its effect on viru• saccharide capsules as their major surface antigens. Pneu• lence in mice is small, although similar capsules may mococci, however, also have autolytic enzymes that break occur on group C streptococci and have greater virulence down cell walls in late growth phases, releasing DNA and than unencapsulated strains. Nevertheless, mucoid group other intracellular components. Intact pneumococci can A strains have been associated with severe disease in also take up genetic material, and are thus autotransform• humans and with rheumatic fever. (24,55) able, a characteristic that appears to have facilitated the Lipoteichoic acids are composed of polyglycero• spread of antibiotic resistance within the species. With phosphate attached to lipids. These surface molecules are few exceptions, streptococci are aerobic and faculatively directly involved in attachment of organisms to host anaerobic. They are cytochrome-negative, -negative, epithelia and are of importance in the initiation of infec• and ferment sugars mainly to lactic acid but not to gas. All tion.<58) Other cellular components are less well defined in streptococci secrete enzymes extracellularly, but those of terms of their role in disease. As in other gram-positive group A have been studied most extensively. bacteria, there is a rigid cell wall structure made from polymers of alternating glucosamine and muramic acid units cross-linked by peptide side chains. This serves to 4.1. Cellular Antigens and Enzymes stabilize the organisms against outside osmotic changes. 4.1.1. Group A Streptococcal Cellular Antigens The peptidoglycan components are highly inflammatory and Enzymes. The major components of group A strep• and may playa role in inciting nonspecific host responses. tococci are the cellular antigens and the extracellular The T proteins, noted above, occur in families that may be enzymes listed in Table 5. M proteins, noted above and shared by a number of M types. The serum opacity factor Chapter 34 • Streptococcal Infections 685 proteins are coexpressed with specific M types and are not type 1, 5, and 19, do not produce NADase and yet are fully shared among M types.(23) The R antigen is an antigenic capable of causing disease. surface protein that occurs in strains of various types but Proteinases of group A streptococci have been care• appears to play no role in virulence or protection. Like fully studied and shown to exert pathological effects in group C and G streptococci, group A and other strep• vitro and in vivo. Their role in human disease has yet to be tococci also have antibody-binding proteins that bind anti• directly established.(60) A specialized peptidase has re• bodies nonspecifically via the Fc fragment, presumably to cently been described that diminishes chemotactic activ• help the organism avoid specific, complement-fixing, ity by inactivation of the C5a complement component. (62) antibody binding.c59) Streptococcal pyrogenic exotoxins (SPE) are the Group A streptococci secrete various substances into erythrogenic toxins responsible for the characteristic rash the surrounding milieu that may contribute to the patho• of scarlet fever. These enzymes have been implicated as genic process. There are two well-described hemolysins factors in streptococcal toxic shock, where they appear to capable of lysing red blood cells and injuring other cell be potent activators of tumor necrosis factor (TNF) and membranes and subcellular organelles.(60) Streptolysin 0 other cytokines.(4,63) There are three antigenic ally distinct is the antigenic, oxygen-labile hemolysin used in the ASO toxins, designated SPE A, B, and C, All group A strepto• test. Streptolysin S is nonantigenic, oxygen-stable, and cocci carry a gene (speB) that codes for SPE B, but it is not responsible for hemolysis at the surface of cultures grown understood why some strains are stronger producers of the on blood agar under aerobic conditions. toxin than others, SPE A and SPE C are encoded by Deoxyribonucleases (DNases) are elaborated by lysogenic bacteriophages, and only those strains infected group A, B, C, and G streptococci.(60) DNase B is the most by the phages are capable of producing toxin. Humans common and most immunogenic of the group A DNases make antibodies to SPE A, B, and C, which appear to and is the basis of the antibody test of the same name. confer toxin-specific immunity to scarlet fever. It is pos• While a pathogenic: role is not established, it is thought sible to have scarlet fever more than once, due to different that these enzymes, along with hyaluronidase and strepto• toxins. The classic determination of susceptibility to scar• kinase, combine to produce the thin pus seen in strepto• let fever is the Dick test.(l) Seldom used today, it is based coccal infections, in contrast to the thick pus often associ• on the observation that patients with antibody to a specific ated with infections due to other pyogenic bacteria.(I) toxin show no response to a small intradermal of Streptococcal hyaluronidases (produced by groups A that toxin (negative Dick test), Susceptible individuals, and C) are capable of hydrolyzing the hyaluronic acid of who have no antibody to neutralize the toxin, develop group A capsules and of mammalian connective tissue. inflammation at the injection site within 24 hr (positive Although formerly called "spreading factor," its biolog• Dick test), SPE A shares structural and physiological ical role remains uncertain with regard either to cell me• similarities with TSST-l, one of the toxins associated with tabolism or to the production of disease.(60) staphylococcal toxic shock syndrome (see also Chapter 33), The streptokinases are antigenic proteins that con• 4.1.2. Group B Streptococcal Cellular Antigens vert plasminogen to plasmin, which in tum lyses fibrin and Enzymes. The group B streptococci differ from clots. Group A streptococci produce either streptokinase group A in that their virulence may be accounted for A, the most common, or streptokinase B. An antibody test principally by capsular polysaccharides rather than pro• based on the former antigen is sometimes employed in the teins. The capsular types, noted in Section 3.4.1 and in clinical assessment of group A disease. A distinctive low• Table 4, are antigenically distinct by virtue of variations in molecular-weight streptokinase, called "nephritis strain• linkages of the same essential sugars. A key feature is that associated protein," has also been identified from group A all have terminal N-acetylneuraminic acid (sialic acid) streptococci recovered from patients with acute neph• residues that are major immunodeterminants, The cap• ritis. (61) sules are anti phagocytic and require specific antibody Nicotinamide adenine dinuc1eotidase [(NADase) for efficient opsonization. The quantity of sialic acid• also called diphosphopyridine nucleotidase (DPNase)] is containing antigen appears to be directly related to size produced by streptococci of groups A, C, and G.(60) Anti• and density of the capsule and to virulence in animal NADase antibodies are produced by the majority of pa• models,(64,65) The capsular material itself appears to in• tients recovering from group A streptococcal pharyngitis, hibit the activation and chemotactic functions of neu• but responses are poor following skin infections. NADase trophils,(66) Many group B strains are also capable of is toxic to leukocytes, but the role of this enzyme in human binding fibrinogen to their surface in a manner that com• infection is not certain, since some serotypes, such as M petes with the nonspecific binding of C3 complement. 686 Part II • Acute Bacterial Infections

The group B antigen is a complex glucitol-containing in structure. Its major antigenic determinant is phospho• polysaccharide associated with the peptidoglycan cell choline, linked to ribitol phosphate, galactosamine, and wall. Antibodies to the group B antigen are generally not other sugars. Antibodies to the phosphocholine moiety protective, presumably because it is covered by capsular protect mice from experimental infection. Although hu• material. A human monoclonal IgM antibody to the group mans make "natural" antibodies to this antigen, opson• B antigen has been described that opsonizes strains of all ization of pneumococci (and presumably protection) is serotypes, (67) but the large amount of antibody required almost entirely dependent on anticapsular antibodies.(76) appears to make it impractical as an adjunctive therapeutic The phosphocholine determinant is also the site of binding agent. for C-reactive protein (CRP), an acute-phase reactant The major protein antigen of group B streptococci is elevated in acute disease. The Forssman antigen is a the c protein, which occurs on all type Ib and some type II membrane teichoic acid with a similar composition, but it and III strains. Antibodies to this antigen are protec• is linked to a lipid, forming what is essentially the lipo• tive,(68) but common variants of the protein apparently teichoic acid of the pneumococcus. confer resistance to intracellular killing by neutrophils. (69) Cell surface proteins, notably a newly described anti• An important property of the c protein may be its ability to gen designated pneumococcal surface protein A (PspA) nonspecifically bind human IgA. (70) The R and X antigens has been identified on essentially all important clinical are rarely seen in human isolates and probably play no role isolates. (32) Although the importance of these proteins in in protection or disease. Also present are lipoteichoic human disease has not yet been determined, this highly acids that are involved with adherence of organisms to variable protein appears to play a role in virulence, and host epithelial cells. antibodies to this antigen are protective in mice against The group B streptococci elaborate a number of multiple capsular serotypes. (77) Humans, including young extracellular enzymes, including hemolysins, CAMP fac• infants, make antibodies to PspA, suggesting its possible tor, DNases, and "neuraminidase. "(60) Pritchard et al. (71) use as a vaccine, as noted below. have recently shown that the enzyme thought for many Enzymes produced by pneumococci include pneu• years to be a neuraminidase is in fact a hyaluronic acid molysin, amidase (the autolytic enzyme that breaks down lyase that has a unique mechanism of action quite unlike cell wall material), neuraminidases, IgA proteases, and a that of hyaluronidases produced by group A streptococci hyaluronidase.(60,78) Although none of these has been con• or pneumococci. A group B streptococcal hemolysin has clusively shown to be associated with virulence, all have been identified that is cytotoxic for mammalian cells in at least theoretical implications. The pneumolysin gene vitro and inhibited by phospholipids common to pulmon• bears extensive amino acid sequence homology to strepto• ary surfactants. (72) The CAMP factor potentiates the activ• lysin 0 and to the theta-toxin of Clostridium peifringens. ity of sphingomyelinase and may have effects on cell Pneumolysin is an intracellular enzyme and is released membranes. Purified CAMP factor appears to enhance the only by cell lysis. It is highly toxic to pulmonary epithelial lethality of live organisms injected into mice.(73) Like cells; it may be important to the pathogenesis of pneu• group A, group B streptococci elaborate a proteinase that monia, but it appears to have a limited effect in experi• decreases chemotactic activity by specifically cleaving mental meningitis.<79) Neuraminidases are directly toxic complement C5a.(74) A pyrogenic exotoxin has recently to mice and may playa role either in modifying epithelial been identified from strains associated with a group B cells during invasion or in direct damage to cells in men• streptococcal toxic shocklike syndrome in infants. (75) ingitis. IgA proteases cleave the Fc fragment from IgA, 4.1.3. Pneumococcal Cellular Antigens and En• making it incapable of preventing adhesion to epithelial zymes. S. pneumoniae is the paradigm of encapsulated cells and possibly also preventing the recognition of IgA bacteria. Its polysaccharide capsules are essential to viru• by tissue macrophages.(60) lence, antibodies against the capsule are the major specific 4.1.4. Components of Other Streptococci. Other defense against infection, and the development of anti• pyogenic streptococci share many characteristics noted body is important in convalescence from disease. The 82 above. All have rigid peptidoglycan cell walls, with var• recognized type-specific polysaccharides vary in compo• ious distinctive or group antigens, and usually with some sition, including linear polymers, branched chains, and form of lipoteichoic acid. Group C streptococci may have teichoic acidlike antigens. The most frequently occurring hyaluronic acid capsules like those of group A. Group G types have been selected for inclusion in the presently streptococci may have the type 12 M protein of group A or licensed vaccines.(3J) similar surface proteins, as well as antibody-binding pro• The C-polysaccharide corresponds to the group car• teins. The group C streptococci from human, equine, and bohydrates of other streptococci but differs significantly porcine sources produce species-specific streptokinases Chapter 34 • Streptococcal Infections 687 that are otherwise similar to those of group A.(SO) A tococci. Exceptions include some pneumococci and group streptokinase derived from group C has been used clini• D streptococci and the enterococci. Although streptococci cally in attempts to clear clotted intravascular catheters, are generally resistant to aminoglycosides, gentamicin is to lyse pleural adhesions in patients with lung infections, sometimes used for its synergistic effect in combination and to help remove clots in patients with coronary artery with a penicillin. Chloramphenicol occasionally has been occlusions. (S/) Group G streptococci also produce strep• used in penicillin-allergic patients, but other drugs, includ• tokinases. We have described a patient with nephritis ing erythromycin, clarithromycin, and clindamycin, are following infection with a group G strain that had a low• considered to be superior for most streptococcal species. molecular-weight enzyme similar to the nephritis strain• Group A and B streptococci have never developed associated protein of group A. (S2) resistance to penicillins, probably because they are not The enteric and oral streptococci are usually unen• naturally transformable, as are pneumococci and entero• capsulated. Streptococci of the "milleri" group appear to cocci. They are somewhat less sensitive to vancomycin require at least 50% of cells to have capsules in order to and cephalosporins, moderately resistant to chloramphen• produce abscesses in experimental animals. Capsule pro• icol, and fairly resistant to aminoglycosides, sulfon• duction can be induced in some species, but capsular amides, and tetracycline. Group B strains have shown materials from this group have not been defined.(S3) Few some tolerance to penicillin, but the clinical significance toxins or noxious enzymes have been described among of such observations is unknown. Tolerance to penicillin the enteric and oral streptococci, but this may be from lack has been suggested as one mechanism by which group A of concerted investigation. Members of the "milleri" streptococci persist after treatment of pharyngitis, allow• group have, at the least, hyaluronidase, deoxyribonu• ing either relapses or asymptomatic carriage to follow.(S6) clease, and various proteinases.(S4) For many of the less Another mechanism is thought to be the protection of virulent streptococci, the inflammatory response to infec• susceptible streptococci by the production of j3-lactam• tion probably relates more to the properties of the cell wall ases by other bacteria in the pharynx or tonsils. (87) Resis• breakdown products than to specific enzymes or toxins. tance to erythromycin occurs in 1-5% of group A strains Characteristics that enable them to cause disease often in most parts of the world; resistance rates, which tend to relate to their ability to adhere to host tissues, such as tooth parallel antibiotic use, as high as 60% have been reported enamel, heart valves or prostheses, or to intravascular in Japan and parts of Europe. catheters. S. mutans, for example, adheres to the pellicle Penicillin resistance in pneumococci has emerged coating the tooth surface by specific protein receptors slowly over the past two decades and has now become a called antigen I1II; adhesion is further facilitated by the frequent and serious problem worldwide. (88) Most of these presence of sucrose. S. mutans also produce extracellular strains have intermediate susceptibility [minimum inhibi• proteases that are capable of breaking down cemental tory concentration (MIC) 0.1-1.0 J,Lg/ml], but highly resis• collagens and other host stubstrates. Caries occur when tant strains (MIC > 1.0 J,Lg/ml), initially reported from the secretion of acids demineralizes the enamel and organ• South Africa and Spain, have now spread throughout isms adhere to and invade the tooth surface.(l1,85) Entero• Europe and North America. Using molecular epidemio• cocci and "milleri" group streptococci are frequently logical methods, one particular resistant clone has been found in mixed infections, especially in association with traced from Spain to Iceland and elsewhere.(46) Span has a anaerobic bacteria, suggesting that additional factors are long history of unrestricted antibiotic use; it has also been required for them to cause disease. Enterococci produce a favored vacationing place for Northern Europeans. The several pheromones that are chemotactic for neutrophils environmental pressure of uncontrolled antibiotic use plus and may contribute to the inflammation associated with increased international travel have contributed dramati• infection. E. faecalis also produces a plasmid-encoded cally to spread of multiple drug resistance. Some isolates hemolysin. Because enterococci are frequently resistant are now resistant to all common antibiotics except van• to common antibiotics, serious enterococcal disease also comycin, rifampin, bacitracin, , and fusidic occurs assuperinfection in patients receiving broad• acid. In parts of South Africa, resistance to rifampin is spectrum antibiotics that may disturb the normal ecology prevalent, because of the widespread use of that drug for of this usually benign organism. treating tuberculosis. In Europe, intermediate and resis• tant strains account for up to 50% of all pneumococcal isolates. In the United States, penicillin resistance rates 4.2. Antibiotic Susceptibility are 20-30%; the proportion of highly and multiply resi• The streptococci are generally quite susceptible to stant strains is about 1%. In areas where resistance to both penicillin, including most oral and "milleri" group strep- penicillins and cephalosporins is prevalent, many physi- 688 Part II • Acute Bacterial Infections

cians now add vancomycin to the initial empiric antibiotic disease, especially as manifested by scarlet fever, has regimen when pneumococcal meningitis is suspected. (88) declined dramatically since the beginning of the century, The National Committee for Clinical Laboratory Stan• as illustrated in Fig. U1) The severity of the disease, dards recommends screening of pneumococci by disk dif• reflected by mortality rates, declined concomitantly. This fusion on Mueller-Hintonl5% sheep blood agar using 1-fLg trend began long before the advent of antibiotics, suggest• oxacillin disks. The criterion for susceptible strains is an ing a decrease in virulence or an increase in host resis• inhibition zone diameter ~20 mm. About half of strains tance, or both. In the 1940s, penicillin became widely with zones <20 mm may prove borderline susceptible available, and deaths attributed to scarlet fever and puer• when retested for MIC by the agar dilution method. (89,90) peral sepsis, the two most common lethal forms of group The basis for resistance among pneumococci is the A streptococcal disease, became a rarity. The number of alterations in penicillin-binding proteins in combination reported cases of streptococcal sore throat increased dur• with changes in the stem peptides on the muramic acid ing the 1950s and 1960s, probably because of increased units of the cell wall matrix.(88,91) There is no evidence for physician awareness of its relation to rheumatic fever, j3-lactamase coding plasmids in pneumococci. Penicillin greater use of throat cultures, and the availability of anti• acts as a false substrate in the cross-linking of cell wall biotics for treatment and prevention. precursors, preventing the formation of normal peptido• Figure 2 shows the number of positive throat cultures glycan chains and rendering the organisms susceptible to and number of cases of acute rheumatic fever and acute damage by osmotic forces or incapable of normal cell glomerulonephritis in private pediatric practices partici• division. Stable chromosomal changes resulting from pating in surveillance studies in Rochester, New York, multiple transformation events have led to penicillin• over a 20-year period. Of approximately 23,000 throat binding proteins with lower binding affinities for pen• cultures done annually, 18-25% were positive for group icillin, while at the same time the predominant stem pep• A streptococci in this relatively stable population. Mean• tides have shifted from straight- to branched-chain pep• while, the number of cases of acute glomerulonephritis tide moieties. The resulting organisms no longer bind declined from nearly 40 in 1967 to an average of 1 case per penicillin in preference to the new cell wall precursors. year from 1981 to 1988. Confirmed cases of acute rheu• Intact peptidoglycan chains are formed. At least three matic fever dropped from 20-28 per year to a very few genetically related groups of resistant strains have been from 1975 through 1985, but they have since begun to rise. identified and show clear indications of clonal ori• Acute rheumatic fever has show a decline and recent gin. (46,50,91) rise in many but not all 10ca1ities.(l4) In Baltimore, be• Enterococci are moderately resistant to penicillins tween 1960 and 1964, the incidence of rheumatic fever alone, because of the intrinsic properties of their penicillin• was 26 per 100,000 among 5- to 19-year-olds. By 1980, the binding proteins. (12,92) Some strains of E. faecalis have rates had fallen to 0.2-0.8 per 100,000 nationwide among also acquired j3-lactamases as a mechanism of resis• whites, with rates several times higher among other ethnic tance.(84) Infections are usually treated with penicillin or groups. Beginning in the mid-1980s, an increase in new ampicillin plus an aminoglycoside, which exert a syner• cases was seen in Utah, Pennsylvania, Ohio, New York, gistic effect against the organisms. Some enterococci have and other areas. Disease incidence peaked in Utah in 1985, developed high-level resistance to gentamicin (MIC > with 18 per 100,000 population age-adjusted for 5- to 17- 500 fLg/ml), but the extent of this problem is not known year-olds, and rates have subsequently declined to about a because most isolates are not routinely tested for suscep• third of that seen in 1985.(3) Of particular interest was the tibility to this drug. Vancomycin-resistant E. faecalis have observation that throughout this period incidence rates recently appeared and may present difficult therapeutic went essentially unchanged in Hawaii(93) and New Zea• challenges, especially in view of their increasing fre• land,(94) where the disease is especially prevalent among quency in nosocomial infections.(12,92) Polynesian children. In a program begun in 1984, the World Health Organization (WHO) Cardiovascular Dis• ease Unit surveyed 16 developing countries and found 5. Descriptive Epidemiology rates averaging 220 cases per 100,000 childhood popula• tion.<95) Highest rates were in Africa (470/100,000) and the Eastern Mediterranean (4401100,000); lowest rates 5.1. Prevalence and Incidence were in Southeast Asia (12/100,000) and the Western Group A streptococcal pharyngitis is one of the most Pacific (71100,000), with the Americas falling in between common acute bacterial infections. The frequency of this (15/100,000). The major problem in the developing world Chapter 34 • Streptococcal Infections 689 is establishing and maintaining effective primary and sec• of about 4 neonatal group B infections per 1000 live ondary prevention programs.(96) This principle applies as births.(IOI) Exact incidence data are very difficult to obtain well to developed areas, such as Miami, Florida, where and interpret, and rates may vary over time, by locality, or underprivileged inner-city children have attack rates of by the nature of populations sampled. An active surveil• 15/100,000, compared to 0.7/100,000 for suburban middle• lance study of an aggregate popUlation of 10 million in class children.(97) four geographical areas was coordinated by the CDC in Deaths from acute rheumatic fever are uncommon 1990. Early-onset disease occurred at a rate of 1.4/100 live today. In developed countries deaths associated with births, late-onset disease occurred at 0.3/1000 live births, chronic rheumatic heart disease continue to occur in per• and adult disease (>15 years of age) occurred in 3.6/ sons who had acute rheumatic fever in childhood and 100,000 popUlation in that year'<15) Few accurate data are develop severe mitral stenosis in the fourth decade or available outside of Europe and North America. Rates later. In 1975, for example, 9,255 of 12,775 deaths attrib• appear to be much lower (about 0.5 per 1000 live births) in uted to rheumatic heart disease were in patients over 50 Scandinavia and the United Kingdom than in the United years of age. (I) The pattern is quite different in developing States and parts of western Europe'<102) Maternal and areas, as in South Africa, where a third of patients have infant colonization rates are similar in Hong Kong, but the mitral regurgitation usually associated with ongoing rheu• neonatal disease rate is 0.6 per 1000 live births.(l03) Mater• matic activity.(98) Left untreated, these lesions develop nal sepsis due to group B streptococci occurred in 0.5-2 into a severe form of pure mitral regurgitation that re• per 1000 deliveries in Alabama. (104) Lowest rates were quires in the first or second decade of life. Degen• seen when particular attention was paid to aggressive erative valvular disease, including mitral stenosis and antibiotic use in mothers undergoing cesarean section mixed lesions, are like those seen elsewhere but tend to delivery. occur at a younger age. The overall annual incidence of invasive group B Acute poststreptococcal glomerulonephritis is cur• streptococcal infections was 9.2 per 100,000 popUlation rently a rare disease, as shown in data from Rochester, for metropolitan Atlanta during 1989-1990.(105) Nearly New York, in Fig. 2. There are no contemporary data rates half of the total number of 424 cases were in adults, and of for nephritis associated with either throat or skin infec• these 68% were in men and nonpregnant women. tions in the United States. Prospective studies in Alabama The incidence of pneumococcal disease is summa• (1966-1969) revealed 91 cases of nephritis relative to 1149 rized in Chapter 28. cases of uncomplicated streptococcal pyoderma treated in Enterococcal infections now account for nearly 10% a clinical setting, for an attack rate of about 8%.(25) of nosocomial infections and for 5-6% of all bacteremias Another change in group A streptococcal disease in in hospitalized patients (see Chapter 25).(12.13) Rates of recent years has been the reappearance of serious acute bacteremic infection are often twice as high on trauma, infections, especially bacteremia and streptococcal toxic surgical, and obstetric-gynecological services. Three shock.(4) Since 1980, the number of septicemic deaths has fourths of enterococcal bacteremias are nosocomial, but increased in the United Kingdom out of proportion with endocarditis is more frequently community-acquired. other streptococcal infections, but precise incidence fig• Case-fatality rates are in the range of 40%, and many of ures are not available. A suvery conducted in Ontario, these patients are debilitated, immunocompromised, or Canada, 1987-1991, studied severe streptococcal disease have serious predisposing conditions. presenting with hypotension in the first 24 hr of obtaining In terms of sheer numbers, S. mutans, the principal a positive culture. The attack rate for 1991 was estimated organism in dental caries, probably infects more persons to be 0.3/100,000 population'<99) than all other streptococci combined. Survey methodology Group B streptococcal infections continue to be and recent studies have been reviewed by Leclercq(lD6) common in neonates, with attack rates of early-onset and Beck.(IO?) Of the 40 to 50% of the population of disease of 2 per 1000 live births in defined popUlations developed countries who regularly visit a dentist, most from Chicago, Illinois, and from Birmingham, Ala• receive treatment related to restoration of teeth or decayed bama.(HlO.lOl) An ongoing study supported by the National tooth substance. Over the past two decades, however, the Institutes of Child Health and Human Development is prevalence of coronal dental caries has declined signifi• currently finding similar attack rates among seven study cantly in developed countries. In the United States, about sites in the United States. Late-onset disease (usually 50% of school-aged children currently have permanent occurring after hospital discharge up to about 3 months of teeth completely free of cavities and restorations.(lD8) age) adds another 2 infections per 1000 births, for a total Inasmuch as dental caries is a chronic disease that 690 Part II • Acute Bacterial Infections

varies within and among populations, several measures of 5.2. Epidemiology and Contagiousness morbidity have been developed. Prevalence, defined as the percentage of a population showing any evidence of Of all the streptococcal infections only scarlet fever caries, may be so widespread as to have little epidemio• has been feared as an epidemic disease in the same sense logical significance. The most commonly used index is as cholera and plague. In most areas of the world, group A that counting the number of decayed, filled, and missing streptococcal disease is endemic, with fluctuations ex• teeth (DFM or DFMT). Because of the difficulty of exam• ceeding the normal prevalence levels occurring sea• ining representative groups of subjects beyond school sonally or sometimes over an extended period. Localized age, population surveys are often standardized at an index epidemics of streptococcal pharyngitis or skin infections age of 12 years.(106) Since the populations of developing and acute rheumatic fever are occasionally reported from countries are skewed toward the younger age groups, who newborn nurseries, nursing homes, day-care facilities, and have fewer caries relative to the older populations in the military installations.(llO.llI) One recent and unusual nurs• developed world, a population-weighted mean DFMT at ery epidemic occurred when infants were infected from age 12 is used for global comparisons. By this measure the clothing that was improperly cleaned in a hospitallaun• WHO can monitor trends from the more than 1000 surveys dry.(ll2) Environmental contamination was thought to be a submitted to the WHO Global Oral Data Bank, set up in source of spread within a day-care facility, with strepto• 1970. The WHO goal of three DFM teeth per person has cocci especially abundant on the nose of a rubber dog been realized in 84 of 148 countries for which data are shared by many of the children.(ll3) currently available. Dental health in industrialized coun• The epidemiology of streptococcal infections re• tries, most of which had moderate to high DFMT rates in flects the ecological features peculiar to the species in 1969, has improved greatly over the past two decades. Mean• question. Streptococci associated primarily with the respi• while, developing countries have seen a rise in DFMT ratory tract, such as group A and the pneumococcus, cause thought to be associated with changes in diet and other infections that are initially related to that portal of entry. factors associated with urbanization. From 1980 to 1986, Of course, some group A strains prefer to colonize the DFMT rates have increased from 1.63 to 2.16 in develop• skin and cause impetigo, while others affect either skin or ing countries and have decreased from 4.53 to 3.82 in throat. The group B streptococci, in contrast, are gut developed countries. (106) Rates also vary within countries. organisms. Asymptomatic gastrointestinal, and to a lesser In the United States, the highest DFMT rates have always extent genitourinary, colonization is common. Their in• been found in northeastern states, with the lowest rates in fections relate to the aberrations induced by pregnancy, south-central states. This has been attributed in part to labor, and delivery, and to the unique conditions of infants differences in natural fluoridation. Further declines in re• in the newborn period. The enterococci are also normal cent years have been attributed to increased use of topical gut organisms, but their infections are more generally fluoride treatments and plastic sealants that physically opportunistic in nature. Group A streptococci are not prevent bacteria from colonizing the tooth cervices. (108) considered part of the normal flora of the respiratory tract. The incidence of dental caries may be estimated from Their presence is generally associated with overt infec• DFMT data, but a more sensitive method makes use of tion. Transmission to other persons is greatest from an individual counts of new decayed and filled surfaces infected individual, and communicability appears to be (DFS) observed over a defined period of time. These dose-related. Nevertheless, a large reservoir of asymp• counts may be further adjusted to calculate annual mean tomatic carriers exists with endemic rather than epidemic DFS rates per 100 surfaces at risk. Using this approach, characteristics. These individuals carry relatively small Glass et al. (109) observed American males 35 to 80 years numbers of organisms. They are at little risk for acute of age in a lO-year longitudinal study. The mean annual disease or sequelae and are probably an uncommon source incidence of new DFS per 100 surfaces at risk was 1.36 of new infection. However, the identification of the carrier and was similar in each of three age cohorts. Within the state, usually defined by the absence of a serological mouth the rate was highest for molars (mean = 2.69), response, is fraught with difficulties that continue to cloud followed by premolars (1.93) and anterior teeth (0.91), and the relationship between colonization and disease.<"4) was higher for upper than lower teeth. The conventional Group B streptococci cause serious disease in the DFMT rate was 23 for these patients at the beginning of perinatal period, but only a small number of infections the study. The DFS incidence rates, however, were similar occur among colonized mothers and infants exposed in to those reported from children aged 7 to 12 years. utero, during, or after delivery. Maternal group B infec- Chapter 34 • Streptococcal Infections 691 tions may be initially subclinical and possibly contribute isolated together with a former carriage type from the to premature labor or septic abortion.(104) Amnionitis may nasopharynx, but only the new type was recovered from be present before the onset of fever or other symptoms. middle ear fluid or other infected sites. In terms of expo• After delivery, a previously asymptomatic mother may sure to new strains, 15% of acquisitions resulted in disease. develop endometritis, usually without bacteremia. Classi• The concept of dental caries as a transmissible infec• cal puerperal sepsis due to group A streptococci, in con• tious disease was drawn from animal studies in the 1960s. trast, was often transmitted via obstetric personnel and S. mutans has been implicated as a major in occurred as a fulminant infection after delivery, sparing caries, and it appears that most infants acquire S. mutans the infant. With group B streptococci, infected infants are strains from their mother. (II) Caufield et al. (0) have con• usually exposed in utero to the serotype carried by the firmed these observations using molecular methods in a mother. Infants with this "early-onset" form of infection prospective study of acquisition and infection. They fur• are usually bacteremic at delivery and become sympto• ther developed evidence for a discrete "window of infec• matic within a few hours of birth.(lOl,IIS) Infection is di• tivity" between 18 and 30 months of age, coinciding with rectly related to the size of the inoculum to which the the emergence of the 20 primary teeth. Children who did infant is exposed, by swallowing or aspirating infected not acquire S. mutans during this period were at much amniotic fluid. Most infants are lightly colonized and at lower risk for caries, at least through 6 years of age. Based little risk for infection, whereas those who are infected are on epidemiological evidence from caries prevalence sur• almost invariably heavily colonized at birth.(lOO,IOI) Some veys, it is postulated that a second window of infectivity infants may acquire organisms via the respiratory tract may exist coincident with the emergence of permanent during transit through the birth canal, or from persons teeth between 6 and 12 years of age. other than the mother, and become symptomatic at a later time. Development of the late-onset form of disease may 5.3. Geographic Distribution be delayed for days or weeks, and only about half of these infants will be infected by an organism acquired at birth or Streptococcal diseases are of worldwide importance. from the mother.(IOI) Group A streptococci appear to be well adapted to humans Pneumococci are often thought of as normal respira• living in temperate or tropical climates, although differ• tory flora, but pneumococcal infections are not oppor• ences in the temporal distribution and perhaps the charac• tunistic in the sense that they are caused by any pneu• teristics of disease may vary. In some tropical areas, group mococcus that happens to reside in the nasopharynx. In a C and G streptococci are more frequently isolated in cases classical investigation, Hodges and MacLeodOl6) reported of pharyngitis than are group A strains. Pneumococci are extensive epidemiological studies at a United States Air the leading cause of bacterial respiratory infection in all Force training facility in 1946. Upon arrival at the base, parts of the world. In some areas, such as sub-Saharan recruits frequently carried pneumococci of serotypes Africa where seasonal epidemics of meningococcal dis• common to the popUlation at large. Within about 6 weeks, ease are common, pneumococcal disease remains en• they acquired one of a small number of "epidemic" types demic and accounts for many cases of meningitis through• prevalent at the base-types 1, 2, 4,5,7, and 12. The peak out the course of the year. As noted above, group B incidence of pneumonia due to these types occurred 4-6 streptococcal carriage is widespread, but infection rates weeks after the entry of a new contingent of trainees. are highest in North America and western Europe, with Although the rate of carriage of the epidemic types was lowest rates reported from the United Kingdom, northern relatively low, the "infectivity factor" (measured by the Europe, and parts of Asia. (102) ratio of infections to the number of carriers) was much Dental caries occur worldwide, but are more com• higher than that of other common types, such as 3, 6, 14, mon in industrialized areas than in developing countries, 19, and 23. In our epidemiological studies in infants, we as noted above.(ll,l06,107) This has been attributed in part also observed a relationship between acquisition and in• to the higher use of sucrose, prepared and refined food• fection. (19) Infants frequently carried types 6, 14, 19, stuffs, and other dietary and social changes associated and 23 for prolonged periods, but neither carriage per se with urbanization. It is mitigated to some extent by the nor overall rates correlated with disease. Most infections, availability of artificial fluoridation in dentifrices and wa• which were due to these same common types, occurred ter supplies and of dental care, especially the use of within a month of acquiring a new type never before sealants and topical fluoride. Caries have always been less carried by a particular child. The infecting type was often common in areas with natural fluoridation. 692 Part II • Acute Bacterial Infections

5.4. Temporal Distribution parallels the markedly seasonal rate of acquisition of new strains.(19,1l7) In the study of Hodges and MacLeod,(116) Group A streptococcal infections follow characteris• there was also a strong correlation of pneumococcal lobar tic seasonal patterns. In northern parts of the United pneumonia with the seasonal peaks of influenza virus States, streptococcal pharyngitis is typically seen over the infection, with about one case of pneumonia for every ten winter months, peaking in February or March, while skin recruits admitted to the infirmary with nonbacterial respi• infections occur mainly in the summer. Figure 3 illustrates ratory disease. this pattern in surveillence data from private pediatric practices in Rochester, New York, for the 12 years 1977- 5.5. Age 1988. In the southeastern states there is both a late fall and a late winter peak of respiratory infection, coinciding with Group A streptococcal pharyngitis is uncommon in the beginning of school in the fall and with increased children under 4 years of age. It increases in frequency as indoor activity or crowding during colder months. Sea• children enter school, peaking at 9 to 12 years of age. sonal variation is less evident in tropical or subtropical These children are the primary source of respiratory infec• areas, although gathering of children at school or other tions that occur among families, and are thus a source of institutions appears to increase the incidence of disease at exposure for parents and other adults in the household. certain times of the year. Streptococcal skin infections are Streptococcal impetigo, in contrast, is chiefly a disease of most common in the rainy season in tropical areas. Such younger children. It is frequently seen in toddlers and conditions favor the exposure of unprotected skin to the children under 4 years and typically reaches a peak inci• assault of minor trauma and the bites of mosquitoes and dence at about 6 years of age. Adolescents tend to be other insects. Organisms present on the skin surface, or subject to milder and often self-limited disease. rarely from the respiratory tract, may be inoculated into Group B streptococcal sepsis or meningitis is essen• damaged skin by itching or scratching. tially limited to neonates and infants under 3 months of Pneumococcal infections tend to peak in winter age and to their mothers around the time of delivery.(7·104) months. The disease incidence is not related to the car• Group B streptococci are a common though sometimes riage rate, which varies only slightly over the year, but disregarded cause of urinary tract infection among adult

Impetigo HI __"._ •••• _IIIIIIII III 140 Scarlet Fever GI 140 III 120 III 120 U 100 100 '0 80 80 ... 60 GI 60 .a 40 E 40 ::s 20 Z 20 0 0 J J J J J J 19n 1978 1979 1980 1981 1982

III 140 140 GI III 120 120 III U 100 100 '0 80 80 60 ...CD 60 .a 40 40 E ::s 20 20 Z 0 0 J J J J J J 1983 1984 1985 1986 1987 1988 Figure 3. The number of cases of scarlet fever (solid lines) and streptococcal impetigo (dotted lines) seen monthly in private pediatric practices participating in streptococcal surveillance studies in Rochester. New York, 1977-1988. The data were kindly provided by Caroline Breese Hall, University of Rochester. Chapter 34 • Streptococcal Infections 693 women, especially during pregnancy. This has been asso• 5.7. Race and Genetic Factors ciated with late abortions and problems of the perinatal No one is spared from susceptibility to streptococcal period. Rarely does an older child or adult develop a infections. Much of the association between race and serious infection in the absence of some compromise of susceptibility can probably be accounted for extrinsic normal host defenses. Among older adults, especially factors, such as poverty, crowding, and lack of medical diabetics, group B streptococci are frequently isolated care. Nevertheless, there is growing evidence that certain from cellulitis and pressure ulcers.(l18) persons within racial groups may have some genetic host Pneumococcal disease is seen in all age groups, but predisposition. Studies of histocompatibility leukocyte principally affects the very young and the very old. antigen (HLA) distributions point to increased risk of Among children, 70% of meningitis and bacteremia oc• rheumatic fever for blacks expressing the DR2 phenotype curs in those under 24 months of age, peaking at 8 to 12 and for whites with the DR4 phenotype.(l24) Agamma• months of age. (119.120) Deaths are also most frequent in this globulinemia and IgG subclass deficiencies are associated age group, with an overall fatality rate of 6%. Pneumococ• with recurrent pneumococcal infection.(l25) Various com• cal infections are least common among adolescents but plement deficiencies, especially that of the second compo• increase in frequency with advancing age. The incidence nent (C2), should also be considered in children with of bacteremic infections reaches 25 per 100,000 among repeated pneumococcal disease. Children and adults with those over 55 years of age, and the case-fatality rate in sickle cell disease are at increased risk because of func• this group is over 80%.(121) tional asplenia, which develops after repeated episodes of Serious infections by enteric and oral streptococci splenic infarction. Down's syndrome and cleft palate are are less subject to the effects of age than to the natural associated with increased frequency of otitis media due to defenses of the host. Low-birth-weight babies, however, pneumococci and other organisms. are increasingly infected by group D and viridans strep• tococci and enterococci, perhaps because of the kinds of interventions required for the management of very prema• 5.8. Occupation ture infants or changes in patterns of antibiotic use. Nosocomial infection caused by enterococci span the Occupation is rarely a factor in the development of range of age, but most community-acquired disease oc• group A streptococcal infections. Physicians, nurses, and curs in infants. (122) laboratory workers in close contact with infected patients Dental caries is a chronic disease that continues or their cultures seldom develop disease. Epidemics of throughout life. Longitudinal studies from the United skin infections have occasionally appeared in meat packers States and from Africa show that rates of development of in the United States and Britain.(l26) Group B streptococci new caries are about the same in adults as they are in are a major cause of mastitis in cattle. Spread is thought to children, despite considerable differences in overall caries occur mainly via the hands of dairy workers from human incidence for the two localities.<109.123) However, as or bovine sources. Consumers of raw infected milk may noted in Section 5.2, there appears to be an age-specific become colonized with group B streptococci, but do not window of acquisition of S. mutans at 18-30 months of appear to be at risk for disease. Group A and C streptococ• age that correlates with subsequent risk of caries develop• cal diseases have occasionally been associated with milk• ment.(lO) borne transmission. Group C infections have also been associated with exposure to horses and other animals. (127) Workers in the pork industry occasionally develop men• 5.6. Sex ingitis due to S. suis, at a rate in the Netherlands of about Sex is not a factor in the development of streptococ• 3 per 100,000, or 1500-fold higher than in the population cal disease, except as it relates to pregnancy and to spe• at large. (128) cific genitourinary infections. The peptostreptococci are recognized in pelvic inflammatory disease, but are rarely 5.9. Other Settings and Predisposing Factors encountered (or looked for) elsewhere. Group B strep• tococci may be transmitted by sexual contact, but genital Family studies of respiratory bacteria have indicated colonization is not associated with symptoms in either that the group A streptococcus and the pneumococcus sex. Colonization may be higher in women during the first enter a family unit most commonly via school-aged chil• half of the menstrual cycle, perhaps because of greater dren. (129.130) These organisms spread rather slow ly to other adherence to vaginal epithelial cells at this time. family members, some becoming colonized and very few 694 Part II • Acute Bacterial Infections

developing overt infection. Spread is often facilitated by spleen is injured most commonly by external abdominal concomitant viral respiratory infections. Socioeconomic trauma and incidentally during abdominal operations not factors, crowding, and substandard housing have fre• directly involving the spleen. Surgical repair, rather than quently been cited as contributing to the spread of these removal, of a traumatized spleen is frequently possible organisms and to the development of acute rheumatic and should always be preferred.(136) Overall, about a fever and bronchopneumonia. Schools and day-care cen• fourth of children with pneumococcal bacteremia, or ters may experience periodic problems with group A meningitis have some underlying condition or host de• streptococci, including the selection of erythromycin• fense abnormality, and risk for these children persists well resistant strains.(13!) Spread of pneumococci generally oc• beyond 24 months of age.(119) Patients with human immu• curs slowly with little consequence in day-care centers, nodeficiency virus (HIV) infection or acquired immuno• but occasional outbreaks of serious disease have been deficiency syndrome (AIDS) are at particularly high risk reported in these settings.(132) of bacteremic pneumococcal infection. (137) Intravenous The military has been associated for over a century drug abuse, also a known AIDS risk factor, is associated with increased risk for developing streptococcal disease, with an increase in group G streptococcal infection. especially acute rheumatic fever and pneumococcal pneu• monia.(lll,116,133) Our present understanding of the epide• miology of rheumatic fever and methods for antibiotic pro• 6. Mechanisms and Routes of Transmission phy laxis date from important studies done in the US Armed Forces during and after World War II. Rates of streptococ• The transmission of streptococci, introduced in Sec• cal pharyngitis are much lower in recruit camps where tion 5.2, depends on such factors as the usual ecological penicillin prophylaxis is routinely used, and rheumatic niche of the species, its occurrence as part of the normal fever cases have recently appeared at installations that flora, and the ease with which it may be carried by hands, discontinued the practice. (Ill) In one report, however, anti• in secretions, or possibly in droplets. The group A strep• biotic prophylaxis was not effective until penicillin-allergic tococci are transmitted principally by direct contact. Con• recruits, who continued to harbor streptococci, were given tagiousness is greatest during acute respiratory infection, oral erythromycin.(133) There may be an incidental effect whereas the chronic carrier is a relatively low risk as an of prophylactic penicillin on rates of pneumococcal pneu• infectious source. This probably reflects the fact that de• monia, but this has not been studied. Pneumococcal vac• velopment of infection requires a fairly large inoculum. cines, however, have been a priority. Nearly 30 years before About 100 organisms are required to infect adult volunteers the current generation of vaccines was licensed in the by directly inoculating the tonsils and pharynx with organ• United States, several purified polysaccharide vaccines isms on a cotton swab. Although streptococci may occur were developed for the military and proven efficacious.(31) in droplets and survive in dust, an individual is unlikely to Nosocomial spread of group A, B, and C streptococci acquire a large enough inoculum to become infected from continues to be reported occasionally, especially from ob• these sources. Streptococci recovered from contaminated stetric and surgical services and newborn nurseries.

Common-source outbreaks of streptococcal disease matic heart disease, mitral valve prolapse, or prosthetic are rarely observed, but group A and C infections have heart valves are at higher risk for developing endocarditis been associated with contaminated foods, such as egg due to otherwise "benign" streptococcal species. In such salad, or with improperly pasteurized milk from cows cases, a prophylactic antibiotic, usually penicillin, is ad• with mastitis. Despite the prevalence of group B strep• ministered just prior to the dental or surgical treatment tococci in bovine mastitis, milk-borne group B infections (see Section 9.2). have not been reported. Skin infections due to group A streptococci are often caused by serotypes different from those associated with 7. Pathogenesis and Immunity throat infections (see Table 3). Streptococci may occur on normal skin but do not cause infection unless there is a 7.1. Pathogenesis break in the cutaneous epithelium. Minor injuries such as scratches, abrasions, cuts, or insect bites may become The development of infection involves a multitude of points of entry'(139) Mosquito bites are an especially com• interrelated bacterial and host factors that vary enor• mon site of inoculation, where organisms are rubbed into mously among streptococcal species. The biological char• the wound during itching. In Trinidad, streptococcal im• acteristics associated with virulence among various strep• petigo may be transmitted by flies of the genus Hippe• tococci are summarized in Section 4; certain host factors lates, which feed on open skin sores. Streptococci from and modes of transmission are noted in Sections 5.9 and 6. the nasopharynx may be transmitted to skin sites, but it is The pathogenic process is not clearly understood for any more common for the skin to be colonized first and the streptococcal disease, but it may be useful to consider throat later. Classical erysipelas, in contrast, is thought to three general stages. be transmitted via the respiratory tract, either from the First, organisms are acquired by the host and either patient or from a caretaker. Erysipelas is occasionally seen succeed in colonizing their preferred sites or are elimi• following superinfection of chicken pox lesions. nated by host defenses at the epithelial surface. For many The group B streptococci causing early-onset peri• streptococcal species, the specific mechanisms of adher• natal infections are those carried by the mother in the ence are known.(11.58) Adherence may be important in the lower gastrointestinal and genitourinary tracts.(7·100.101.115) establishment of colonization but is not necessarily a Organisms may enter the amniotic cavity following rup• property that distinguishes virulent from commensal spe• ture of amniotic membranes, but the fetus may become cies or strains. To ward off bacterial invasion, the host has infected with membranes intact. Although rupture of epithelial barriers, mucous layers, and secretions contain• membranes for greater than 12 hr is a recognized risk ing enzymes and antibodies. factor for ascending infection, the duration of labor is also The second stage begins when organisms succeed in important, perhaps because of the entry of organisms via breaching local defenses and enter the epithelial and sub• microscopic defects in the membranes. Among twins, epithelial tissues, or, in the case of S. mutans, get into and who have a higher rate of infection than singletons, it is through the tooth enamel. Most of the acute pathological usually the first twin who is closer to the source of infec• effects of group A streptococci occur at this stage by tion and at greater risk. Once the streptococci have entered causing pharyngitis or skin infection, with invasion of the the amniotic fluid, they proliferate rapidly and are aspi• submucosal or subepidermal layers. This is frequently rated or swallowed by the fetus. Late-onset infections may accompanied by lymphadenitis but rarely progresses to have a maternal source in about half of cases, with coloni• bacteremia. In pneumococcal pneumonia and in otitis zation occurring at delivery. (101) Other infants may acquire media, the initial insult is not a direct breach of epithelium streptococci later from persons outside the immediate but rather the invasion of a normally sterile compartment; family, presumably via the oral or respiratory route. symptoms of disease ensue as organisms multiply and Enteric and oral streptococci are part of the normal induce inflammation in surrounding tissue. The host re• flora, acquired early in life from the mother and family sponds with nonspecific secretory and serum forces, in• members. They generally cause opportunistic infection cluding the release of vasoactive and chemotactic media• only after perturbations of normal defenses. Nosocomial tors, activation of the alternative complement pathway, infections are usually due to a patient's own flora. Tran• and with the mobilization of neutrophils and tissue macro• sient bacteremia may occur with dental manipulation, phages. Eventually, specific secretory and serum anti• transurethral prostate resection, or gynecological and gas• bodies develop and contribute to resolution of the disease. trointestinal surgery. Patients with known history of rheu- The third stage is systemic infection, in which organ- 696 Part II • Acute Bacterial Infections

isms multiply in blood and tissues. Severe streptococcal with the human pathology, where there is often minimal infections, including streptococcal toxic shock, depend on inflammatory response despite the presence of bacteria in the organism's ability to evade host defenses until it estab• the lung or other tissue. (69) lishes a sufficient mass of growth to cause systemic mani• The pathogenesis of the nonsuppurative sequelae of festations. The M proteins protect against phagocytosis group A infections has yet to be fully elucidated. Several and also down-regulating complement activation on the examples of the cross-reactivity between M proteins and bacterial surface.(53) An enzyme that inactivates comple• components of heart, brain, and connective tissue have ment C5a decreases chemotaxis and secondary inflamma• now been convincingly confirmed and add weight to the tory responses. (62) Spread of infection within the tissues long-held hypotheses of autoimmune mechanisms for may be facilitated by the action of hyaluronidase and rheumatic valvular disease/55) Sydenham's chorea,(56) proteinases. Shock is probably mediated by TNF-a, IL-II3, and skin manifestations.(57) Although multiple complex and IL-6, all of which may be induced by pyrogenic toxins factors appear to be involved in disease process, these and (SPE), streptolysin 0, and cell wall breakdown products. other studies have identified M protein epitopes that cross• Further alterations in host physiology occur by cytokine react with myosin, DNA, and a-helically coiled proteins activation and by direct and indirect effects on hemo• such as tropomyosin, actin, and keratin.(142) Antigenic dynamics, metabolism, and the function of individual mimicry between cell wall carbohydrate moieties and organs.c4) cytokeratin(57) may eventually help explain the occur• Some of the mechanisms thought to be involved in rence of erythema marginatum, subcutaneous nodules, acute group B streptococcal sepsis have been studied in rheumatic arthritis, and perhaps streptococcal-associated vitro and in animal models. Early-onset infections appear guttate psoriasis. The diverse manifestations of acute to begin in utero, and it is suspected that the organisms rheumatic fever might be explained in part by the specific• gain access to the circulation by breaching the gastrointes• ity and titer of antibodies cross-reactive with different tinal or pulmonary epithelial barriers. In a monkey model tissue components. In a similar fashion, acute glomerulo• of intrauterine infection, aspirated streptococci were nephritis may involve the development of antibodies that found to be actively taken up by pulmonary alveolar cells. cross-react with basement membrane collagen and lami• These cells acted as nonprofessional phagocytes, but were nin.(l43) The cationic charge of the antigens may also incapable of killing the organisms, and tissue invasion influence their affinity for the glomerular basement mem• rapidly ensued.(l40) In a model of bacteremia, an immedi• brane and the nature of immune complexes formed. An• ate effect of intravenous infusions of washed heat-killed other feature of nephritogenic streptococci is the presence group B streptococci in piglets is the increase in pulmon• of a nephritis strain-associated protein. (6\) This distinctive ary artery pressure, mimicking that observed in septic low-molecular-weight streptokinase is a plasminogen ac• neonates.(l41) The magnitude of pulmonary hypertension tivator and could induce proliferation of cells, release was higher with small- or capsule-deficient organisms of inflammatory products, and activate complement, than with the fully encapsulated organism and was greater thus contributing to known pathological features of the in the presence of type-specific antibodies. These obser• disease. vations suggested that group B streptococci causing dis• The pathogenesis of dental caries, recently reviewed ease have mechanisms to evade the inflammatory responses by van Houte,(ll) involves a dynamic relationship among of the host and, conversely, that early manifestations of dental plaque organisms, dietary carbohydrates, and mu• severe disease depend on the inflammatory response me• cosal host defenses. Dietary carbohydrates favor the diated by both specific and nonspecific host factors. In the growth of S. mutans and lactobacilli, which in tum facili• piglet model the hemodynamic response was associated tate the lowering of pH, attachment of organism to dental with release of thromboxane, and the response could be surfaces, and demineralization of tooth emanel. blocked with indomethacin, a cyclo-oxygenase inhibitor, and dazmagrel, an specific inhibitor of thromboxane syn• 7.2. Immunity thesis. Similar drugs could be useful clinically but remain experimental at present. Other investigators have demon• Specific immunity to streptococcal infections is strated a profound antichemotactic effect of the group B thought to depend on the development of antibodies to type III capsular polysaccharide(66) and an inhibitor of capsular and other surface determinants. Antibody assays C5a,(4) both of which may decrease the nonspecific host for various streptococcal antigens have been noted in responses, prolonging the time for organisms to multiply Section 3.4.2, and current developments in streptococcal and establish infected foci. These observations correlate vaccines are further discussed in Section 9.6. Although Chapter 34 • Streptococcal Infections 697 most of our knowledge of the immune response relates to II, and III in a defined population.(7) Thus, the vast major• the occurrence of antibodies in the serum, recent studies ity of infants are "antibody deficient," whether colonized of mucosal immunity suggest that the first line of host or not, yet only a small number develop disease, even defenses are at the local level. The precise role of secre• when exposed to infected amniotic fluid in utero.(146) The tory antibodies in preventing, modifying, or eradicating presence of mucosal antibodies may modify colonization, bacterial colonization is not presently understood. Con• but so far a clearly defined role for secretory immunity is versely, the effects of bacterial antigens at respiratory and not apparent. gastrointestinal sites are poorly understood in regard to Most of our knowledge of pneumococcal immunity the systemic antibody response and the development of comes from studies of purified polysaccharide vaccines.(31) autoantibodies. In some cases it is likely that the organ• Adults respond well to most of the antigens, but infants isms have developed a form of mimicry to confuse or respond poorly. Children over 2 years of age have more evade the immune response of the host. Many strepto• consistent responses but still respond poorly to types cocci have antigens that cross-react with other organisms, common in childhood illnesses, especially types 6 and 14. common foodstuffs, or components of the host's own Although repeated doses of purified (unconjugated) cap• tissue. Antibodies undoubtedly have functions other than sular vaccines produce little or no booster effect, systemic protection against disease. They are known to be impor• tolerance does not appear to develop in humans. Efforts to tant in the recovery from established infection and prob• improve the immunogenicity of vaccines by coupling the ably function in the removal of antigens from local and polysaccharides to protein carriers appear to elicit T• systemic sites. helper-cell cooperation and greatly improve the immuno• Assays for group A streptococcal antibodies (Table genicity of these antigens in young children. (147.148) Theo• 5) are used clinically to determine if a patient has had a retically, this approach should also increase the propor• recent infection.(52) Although humans normally make an• tion of IgG antibodies. The B-cell response can be tibodies to streptolysin 0 and other extracellular compo• monitored by enumerating the peripheral blood leuko• nents, only antibodies to M proteins are associated with cytes that secrete specific antibodies at about 7 days after protection against subsequent disease.(53) Serum IgG anti• systemic immunization. (149) The majority of cells secreted bodies to M proteins arise in response to infection or IgA antibodies, although the later serum response was immunization and can initiate bactericidal activity in predominantly IgG and IgM. The secretory antibody re• whole blood opsonophagocytic assays. These antibodies, sponse was relatively modest. There is no consensus as however, are not as efficient as secretory IgA antibodies in to what constitutes a protective serum antibody level, protecting mice against infection via the intranasal route. whether IgG is required in preference to IgM antibodies, Intranasal immunization of volunteers with purified M or what role secretory antibodies play in vaccine-induced protein resulted in greater resistance to colonization with immunity.(31) live streptococci than did subcutaneous immunization, and serum antibody response was not a reliable predictor of resistance to pharyngitis. At present, group A vaccines 8. Patterns of Host Response remain experimental, but it appears that local immune mechanisms may be more efficiently utilized and less 8.1. Clinical Features likely to result in systemic side effects. Antibodies to the capsular polysaccharides of group The manifestations of streptococcal diseases are re• B streptococci are thought to mediate protection against markably diverse. Their clinical presentation, diagnosis, systemic invasion. This concept is based on the finding and therapy are discussed in detail in many of the medical, that few infants with group B streptococcal disease have pediatric, and infectious disease textbooks. The most antibodies to the offending type, and that antibodies are common and most important diseases caused by the major protective against bacterial challenge in animal models.(144) streptococcal group are listed in Table 6. Diseases associ• Naturally occurring antibodies in mothers are often of the ated with other streptococci are noted in Tables 1 and 2. IgM class and do not readily cross the ,(145) and The typical form of group A streptococcal respira• less IgG antibody is transferred to the premature than to tory disease in children and adults is acute exudative the full-term fetus. Despite the presumed importance of pharyngitis. The onset is abrupt, with fever, chills, a sore antibodies, it should be pointed out that the prevalence of throat with pain on swallowing, malaise, and headache, group B streptococcal antibodies is generally low, with often with abdominal pain, nausea, or vomiting. On physi• about 6% of cord sera having >2 J.1g/ml against types la, cal examination, the pharyngeal mucosae are erythema- 698 Part II • Acute Bacterial Infections

tous, edematous, and streaked with a purulent nonadherent fulminant form of cellulitis that appears as an elevated exudate over the tonsils or posterior pharynx; petechiae erythematous lesion with a rapidly advancing well-demar• may be present. The anterior cervical lymph nodes may be cated border. Erysipelas often involves the face, a surgical enlarged and are usually acutely tender. In young children wound, an umbilical stump, or a chicken pox lesion. The the findings may be less specific, often with fever and patient is febrile, toxic, and may be bacteremic. Necrotiz• lymphadenitis but relatively little inflammation of the ing faciitis is a deep-seated infection of subcutaneous upper respiratory mucosae. Mild or subclinical infection tissue that destroys fascia and fat, usually sparing skin and may occur at any age and may be missed. This is of muscle. The patient may be diabetic or otherwise debili• concern because up to half of patients developing rheu• tated. Recently reported cases have occurred mainly in matic fever do not give a clear history of an antecedent previously healthy individuals who had trivial or inap• sore throat. With scarlet fever the pharyngitis is accom• parent trauma at the affected site. A hallmark, though panied within about 24 hr by a fine red exanthem begin• nonspecific, is the rapid progression from tenderness to ning on the trunk and intertriginous areas, later spreading severe pain at the site of infection. Infections may become to the extremities. The face is usually spared, but the gangrenous and require surgical debridement or fasci• tongue may be inflamed, with a "strawberry" appearance. otomy.(4) Careful auscultation of the heart should be part of the Streptococcal toxic shock has been observed with physical examination on all patients with acute strep• increasing frequency in Europe and North America during tococcal sore throat or scarlet fever. the past 5 years.(4.150) Persons may be affected at all ages, Streptococcal impetigo may appear as single lesions usually without predisposing or underlying diseases. of the epidermis, frequently on the lower extremities, Most cases involve a skin or soft tissue focus of infection spreading to other areas as new insect bites or breaks in or pneumonia (as in the case of puppeteer Jim Henson), the skin become infected. Early lesions are pustular and and most patients are bacteremic. In children a large rapidly develop into mature lesions about I cm in diameter proportion of cases are associated with infected chicken with a characteristic honey like crust. Lesions may be• pox lesions. Proposed criteria for diagnosis of streptococ• come concomitantly infected by streptococci, which may cal toxic shock are given in Table 7.(150) This syndrome be resistant to penicillin therapy. Erysipelas is a serious differs from other serious streptococcal infections, and to

Table 6. Diseases Associated with Major Streptococcal Groups

Group A streptococci Group B streptococci Pneumococci Enterococci

Most common Early-onset neonatal disease Infants and children Nosocomial Pharyngitis/tonsillitis Undifferentiated sepsis Otitis media Bacteremia Scarlet fever Meningitis Conjunctivitis Intra-abdominal infection Impetigo/pyoderma Pneumonia Pneumonia Surgical wounds Cellulitis Bacteremia Bacteremia Bum wounds Less common Maternal infections Meningitis Vascular catheter Toxic shock syndrome (Table 7) Amnionitis Epiglottitis Urinary tract infection Peritonsillar abscess Endometritis Adults Postpartum infections Mastoiditis Urinary tract infection Sinusitis Community acquired Sinusitis Bacteremia/sepsis Pneumonia Urinary tract infection Otitis media Septic abortion Pleural empyema Endocarditis Erysipelas Bacteremia Endocarditis Biliary infection Pneumonia/empyema Late-onset neonatal disease Meningitis Pel vic infection Puerperal sepsis Meningitis Endocarditis Meningitis Bacteremia/sepsis Endocarditis Bone and joint infection Proctitis Skin and soft tissue infection Vulvovaginitis Otitis media Nonsuppurative sequelae Omphalitis Acute rheumatic fever Acute glomerulonephritis Chapter 34 • Streptococcal Infections 699

Table 7. Proposed Criteria Table 8. Jones Criteria (Revised) for Guidance for Diagnosis of Streptococcal Toxic Shocka in the Diagnosis of Acute Rheumatic Fever, as Recommended by the American Heart Association I. The isolation of group A streptococci A. From a normally sterile site, such as blood, CSF, surgical Major manifestations Minor manifestations wound, pleural fluid, etc. B. From a nonsterile site, such as throat, open wound, or super• Carditis Clinical ficial skin lesion, or vagina Polyarthritis Fever and Chorea Arthralgia II. Clinical signs of severity Erythema marginatum Previous rheumatic fever or rheumatic A. Hypotension; systolic blood pressure"" 90 mm Hg in adults Subcutaneous nodules heart disease or < 5th percentile for age in children Laboratory and Acute phase reactions: B. Two or more of the following: abnormal erythrocyte sedimentation I. Renal impairment evidenced by elevated creatinine ~ 2 mg/ rate, C-reactive protein, or dL (177 fLmolelliter) or twice the upper limit of normal for leukocytosis age; or, for patients with preexisting renal disease, ~ 2 times Prolonged P-R interval baseline level Supporting evidence of streptococcal infection: 2. Coagulopathy: thrombocytopenia « IOO,OOO/mm3) or dis• Positive throat culture for group A streptococcus or positive rapid seminated intravascular coagulation, defined by prolonged streptococcal antigen test clotting time, low fibrinogen, and presence of fibrin degrada• Increased or rising antistreptolysin 0 or other streptococcal antibody tion products The presence of two major, or one major and two minor, manifestations 3. Liver involvement: elevated liver enzymes or total bilirubin plus evidence of a preceding streptococcal infection indicates a ~ twice the upper limit of normal for age; or, for patients high probability of rheumatic fever. with preexisting liver disease, ~ 2 times baseline level Manifestations with a long latent period, such as chorea and late-onset 4. "Adult" (acute) respiratory distress syndrome (ARDS), de• carditis, are exempt from the latter requirement. The WHO Study fined by onset of diffuse pulmonary infiltrates and hypox• Group recommends that the following groups be considered emia in absence of cardiac failure; or evidence of diffuse separately and exempted from the Jones criteria: "pure" chorea, capillary leak manifested by acute generalized edema, or insidious or late-onset carditis, and rheumatic recurrence. (IS]) pleural or peritoneal effusions with hypoalbuminemia 5. Generalized erythematous macular rash, which may de• squamate 6. Soft tissue necrosis including necrotizing fasciitis, myositis, or gangrene or obvious streptococcal infection.(3,151) Because of diffi• A definite case is defined by isolation of group A streptococci from a culties in making the diagnosis, other conditions, such as normally sterile site (IA) plus hypotension (lIA) and supporting clinical signs of severity (lIB). A case is defined as probable if the culture was collagen-vascular diseases and infective endocarditis, from a nonsterile site (IE) and it fulfills the clinical signs of severity (IIA must be considered whenever acute rheumatic fever is + B), when no other etiology for the illness can be identified. suspected. Acute glomerulonephritis presents fewer diag•

"Adapted from The Working Group on Severe Streptococcal Infections.(l50) nostic problems. A recent skin or throat infection is usu• ally evident by examination, history, culture, or antibody tests. The urine is dark, containing many red blood cells and casts. The patient usually has edema and elevated some extent from staphylococcal toxic shock, by the rapid blood pressure; the blood urea nitrogen and creatinine are development of hypotension and multi organ failure early usually elevated and the C3 complement level is low. With in the course of streptococcal toxic shock. appropriate acute care, nearly all patients have a complete The nonsuppurative sequelae of group A infections recovery. may present acutely or insidiously. Acute rheumatic fever Group B streptococcal disease in the neonate usually varies greatly in its manifestations, with the diagnosis begins in utero with nonspecific symptoms appearing being made with the guidance of the Jones Criteria (up• within the first few hours of birth.<101,115) Unexplained dated in 1992),051) described in Table 8. The onset is apnea, respiratory distress, temperature instability, or typically abrupt, with fever and polyarthritis. Myocarditis poor feeding may be the only clues to early-onset disease. or valvulitis, most commonly involving the mitral valve, Infection usually takes the form of undifferentiated sepsis occurs in about half of patients suffering their first attack. with, or more often without, meningitis. The disease is Carditis may be the only major manifestation in some well advanced by the time hypoxia, cyanosis, acidosis, or patients and may develop insidiously, presenting as heart vascular collapse becomes obvious. Lung involvement is failure without any clear history of prior rheumatic fever frequent, but the chest X ray is typical of hyaline mem- 700 Part II • Acute Bacterial Infections

brane disease more often than of discrete pneumonia. irritability or inconsolable crying, poor feeding, or vomit• Similarly, there is rarely a CSF pleocytosis even when ing. Patients presenting with a second episode of men• bacteria are recovered from the spinal fluid. In general, the ingitis must be suspected of having a CSF leak, skull inflammatory response parallels the maturity of the infant, fracture, or immunologic deficiency. Pneumonia in chil• the specificity of clinical signs and symptoms, and to dren is similar to that seen in adults, but classic features of some extent the prognosis. Late-onset infections, occur• chills, hacking cough, pleuritic pain, and rusty sputum ring beyond the immediate newborn period, often tend to may be subdued or absent. Bacteremia in children is be more localized and have a better outcome. Meningitis associated with pneumonia in about a third of cases, with is common, but sepsis without meningitis is frequently otitis media in another third, and the remainder with no seen. (101) Bacteremia or meningitis may be associated with focus of infection. (119) While most infants with bacteremia an infective focus, such as omphalitis, otitis media, or present with fever, leukocytosis, and a clinically apparent osteomyelitis. The long-term outcome of infants who focus of infection, some have occult bacteremia with few survive group B streptococcal meningitis is generally physical findings and a marginal leukocytosis. good. Very occasionally, neonates develop similar disease due to group G streptococci or pneumococci. Maternal 8.2. Diagnosis group B streptococcal disease may occur during gestation, notably urinary tract infections and septic abortion. (104) The isolation and identification of streptococci from Infection around the time of delivery, especially amnion• properly cultured infected sites provides the definitive itis, is a threat to both fetus and mother.(104.146) Endome• means of establishing the diagnosis. A careful evaluation tritis and bacteremia are the most frequent postpartum of the patient is essential in forming an accurate clinical infections. Endocarditis is an unusual complication of diagnosis, after which the physician must decide what perinatal infection or septic abortion and is more often sites are to be cultured and what ancillary tests are appro• seen in older individuals with some underlying heart dis• priate. Streptococcal pharyngitis cannot be reliably diag• ease or other predisposing condition. (152) nosed without a throat culture or direct antigen detection, Group B streptococcal disease also occurs in adult because many other agents may cause acute pharyngitis. men and nonpregnant women. A recent survey of invasive Conversely, an asymptomatic carrier may have a positive group B infections in metropolitan Atlanta hospitals in• throat culture coincidental with a viral pharyngitis. It is in cluded skin, soft tissue, or bone infections (36%), bacte• the best interest of the patient and the community to avoid remia without focus (30%), urosepsis (14%), pneumonia prescribing antibiotics without a specific indication; it is (9%), and (7%).(105) Another excellent clinical also preferable to treat a positive throat culture rather than series, which also included data on group A, C, F, and G risk untoward sequelae. In some cases, however, it is streptococcal infections, found that the case mortality rate valuable to confirm the diagnosis by antibody tests and was 31 % among adults with group B streptococcal bacte• follow-up cultures. The efficacy of treatment regimens remia. (152) Two thirds of all patients were over 50 years depends on accurate etiologic diagnoses. Patients with of age, 22% had primary bacteremia, 25% had underlying recurrent infection may actually prove to be chronic car• nonhematologic malignancies, and 19% had diabetes riers or have mUltiple disease episodes due to different mellitus. streptococcal serotypes. A definitive diagnosis is needed There is now good evidence that group C strepto• for the clinical management of patients with nephritis or cocci are a cause of endemic pharyngitis in adults in open symptoms suggesting rheumatic fever. Patients with toxic populations.(153) Of the several streptococci falling into shock syndrome require a precise bacteriologic diagnosis serological group C, it appears that large-colony S. equisi• by cultures of blood or other materials, because Staphylo• milis is more likely to be associated with clinical disease coccus aureus is even a more common etiology, and than the tiny-colony S. anginosis ("milleri group").(154) treatment may require use of different antibiotics. The presence of these organism must be determined by The microbiological diagnosis of other forms of throat culture, because the rapid streptococcus antigen streptococcal disease is no less important, inasmuch as it detection kits are specific for group A streptococci. directs both the clinical approach and the choice of anti• The clinical features of pneumococcal disease vary biotics. Blood cultures may be indicated when infection is with the site of infection and the age of the patient. suspected in the absence of an obvious infected site, Meningitis in young infants does not commonly present especially for those at risk for nosocomial disease and with neck stiffness and headache, as it does in adults, but infants who may have occult bacteremias. Cultures of more often with nonspecific symptoms, such as fever, blood, spinal fluid, skin, lung or empyema, or sinus or Chapter 34 • Streptococcal Infections 701 middle ear fluid may be required to confirm the appro• amoxicillin and dicloxacillin, are also effective but are priateness of antibiotics selected empirically upon suspicion more expensive and offer no particular advantage. The of infection. While most streptococci remain susceptible older oral cephalosporins (cephalexin, cefaclor, ceph• to the penicillins, some pneumococci are intermediate or radine, cefadroxil) are effective in a number of conven• resistant, as are many oral and enteric species. With the tional lO-day dose regimens. Several newer cephalo• exception of streptococcal pharyngitis, cultures of normal sporins (cefprozil, cefpodoxime, loracarbef) are equally carriage sites, including the nasopharynx and lower bowel, effective; 5-day therapeutic regimens are currently under are rarely useful in making an etiologic diagnosis of investigation but will not be recommended without fur• clinically diagnosed infection. Otitis media, for example, ther evaluation. Erythromycin is a well-established alter• is frequently caused by the pneumococcus, but pneu• native drug for penicillin-allergic patients, except in some mococci are frequently isolated from the nasopharynx of areas of eastern Asia or eastern Europe where resistance children with otitis media due to Haemophilus injluenzae. may be a problem. Clindamycin is effective but is costly Similarly, many infants are colonized by group B strep• and has a small potential risk of pseudomembranous en• tococci at delivery, but relatively few are infected. In terocolitis. Tetracyclines, sulfonamides, and chloram• some instances, however, it may not be possible to obtain phenicol are not effective. a definitive culture, as is often the case in pneumonia. A Control of streptococcal infections within popula• growing pneumococci, in a patient with an tions has been an effective means of reducing exposure in alveolar consolidation on chest X ray and a typical clinical households and institutional settings. Mass prophylaxis course, supports the diagnosis of "putative" pneumococ• with benzathine penicillin has been used in some epidemic cal pneumonia. situations but is now chiefly confined to certain military populations(lll) (see Section 5.9). Eradication of phar• yngeal carriage of group A streptococci using oral anti• 9. Control and Prevention biotic regimens has been attempted with varying degrees of success. Oral clindamycin for 10 days is the currently 9.1. General Preventive Measures accepted regimen. (110) Another regimen is benzathine pen• Personal hygiene, adequate nutrition and housing, icillin plus rifampin for the last 4 days of therapy. Short health education, and access to medical care are all impor• 4-day courses of either rifampin or cefixime were some• tant factors in prevention of streptococcal diseases. In• what effective in adults but less so in children. Patients spection of food and milk production and proper pasteur• with symptomatic streptococcal sore throat may remain ization of dairy products are taken for granted in most infectious for 24 hr after the onset of therapy and should developed countries but remain problems in certain areas. not return to work, school, or day care before completing a Strict asepsis is required in surgical and obstetric proce• full 24 hr of antibiotic therapy.(l38) dures. Simple infection control measures, especially hand Secondary prevention consists of the regular admin• washing, must be continually encouraged, and attention istration of antibiotic to persons who have had rheumatic must be paid to the health of hospital employees working fever in order to prevent subsequent group A infections in patient areas. that could trigger recurrent attacks or exacerbate existing rheumatic heart disease.(20) Secondary prophylaxis is cost-effective, reduces the risk of recurrence, and in many 9.2. Antibiotics in Treatment and Prevention patients allows for healing of valvular damage occurring of Group A Streptococcal Disease in the initial attack. Long-acting intramuscular penicillin Primary prevention of acute rheumatic fever consists is usually given at monthly intervals. Results of a 12-year of identifying and treating persons with acute streptococ• controlled trial have now shown that intramuscular ben• cal pharyngitis, as described in a practice guideline re• zathine penicillin is more effective given every 3 weeks, cently developed by the Infectious Disease Society of compared to every 4 weeks, and should be recommended America. (20) Antibiotic therapy is aimed at eradicating especially in areas where rheumatic fever is more preva• streptococci from the respiratory tract. Shulman et al. (155) lent.(l56) Alternatively, oral penicillin may be given daily, make the case that penicillin remains the drug of choice but lack of compliance is a major problem. Patients unable for treatment of streptococcal pharyngitis. Penicillin may to take penicillin may be given a sulfonamide or erythro• be given as a single intramuscular injection of (long• mycin. The duration of secondary prophylaxis is not cer• acting) benzathine penicillin or as a lO-day course of oral tain but must be tailored to the individual. Patients with phenoxymethyl penicillin. Other oral penicillins, such as valvular rheumatic heart disease are given prolonged, 702 Part II • Acute Bacterial Infections

even lifelong, prophylaxis. Those without cardiac in• popUlations. Prompt treatment of minor skin trauma and volvement should have prophylaxis for at least 5 years and insect bites with topical antibiotic ointment has been at least through age 18 years. Prophylaxis may be safely shown to reduce the occurrence of streptococcal skin discontinued in young adults without carditis, provided infections and could reduce the risk of subsequent neph• that they have adequate medical follow-up and prompt ritis. (139) culture and treatment of pharyngitis episodes.(157) Patients with rheumatic carditis as part of their initial attack are at 9.3. Surgical Approaches to Recurrent Group A greater risk for more serious carditis recurrences and Streptococcal Disease should be given prophylaxis well into adulthood and per• haps for life. Tonsillectomy or tonsillectomy with adenoidectomy Patients who have had isolated chorea as the only are frequently performed because of recurrent throat in• manifestation of rheumatic fever appear to be at much less fections. Although children who have surgery experience risk for carditis during subsequent recurrences. Most au• fewer throat infections over the subsequent 2 years, the thorities recommend that these patients receive prophy• difference in rates compared to controls is not impressive. laxis until age 21 or for at least 5 years, whichever is These findings were confirmed by Paradise et al. (160) in a longer. Some patients have a syndrome of poststreptococ• carefully controlled study with stringent entry criteria. cal reactive arthritis without fulfilling Jones' criteria. A Surgical intervention was beneficial for severely affected few such patients have been described who had silent or children over at least the 2 years following surgery. Never• delayed mitral insufficiency, and one patient without ini• theless, a substantial proportion of those managed non• tial cardiac involvement developed acute rheumatic fever surgically had relatively little throat infection during the 18 months later.(l58) It has been suggested that these pa• period of study, and the actual reduction in group A tients should receive prophylaxis, or alternatively receive streptococcal infection rates was small. Their results ap• prophylaxis for up to 1 year at which point it may be peared to "justify but by no means to mandate the perfor• discontinued if no evidence of carditis develops.(20) mance of tonsillectomy" in carefully selected children. Patients with rheumatic heart disease, as well as Treatment should be individualized and should be consid• others with prosthetic valves, other valvular lesions, and ered only for severely affected children. More clearly probably mitral valve prolapse, are at risk for developing defined indications for surgical intervention include pa• infective endocarditis when undergoing dental or surgical tients with peritonsillar abscess or severe obstructive manipulations. Since the usual secondary prophylaxis symptoms. regimens are inadequate for preventing endocarditis, ad• ditional short-term is required for 9.4. Intrapartum Chemoprophylaxis against Group dental procedures that cause bleeding; when gingival dis• B Streptococcal Disease ease is present; for respiratory procedures including ton• sillectomy, adenoidectomy, bronchoscopy, or mucosal Efforts to prevent neonatal group B streptococcal biopsy; or for genitourinary or gastrointestinal proce• infections have evolved over the past decade from small dures, such as prostate resection or intestinal biopsy. Rec• clinical trials to clinical care guidelines now adopted by ommended antibiotic regimens vary and are updated peri• the major US obstetric and pediatric societies. Because odically.(IS9) High-risk patients, who have prosthetic valves, most neonatal infections begin in utero, a dose of "pro• severely damaged native valves, or a history of previous phylactic" penicillin given to the infant at delivery did endocarditis, are usually given penicillin or ampicillin little to stem the progress of established disease. (llS) A plus gentamicin, to cover oral or enteric streptococci as more effective approach, reported in a landmark study by well as other organisms. Antibiotic doses are given I hr Boyer and Gotoff,(16l) was based on the use of ampicillin prior and 6 hr after the procedure. "Standard-risk" pa• given during labor to selected women who were colonized tients are usually given only a penicillin for dental manip• by group B streptococci and had one or more risk factors ulations, but an amino glycoside is added for genitourinary associated with infection in neonates. This approach was or gastrointestinal procedures. Patients allergic to pen• highly focused, limiting antibiotic exposure to a small icillin or who are on long-term penicillin prophylaxis are proportion of mothers but offering no protection to many given erythromycin or vancomycin. neonates, whose mothers may present with no risk factors. The prevention of acute glomerulonephritis by anti• Because oflogistical difficulties in obtaining and process• biotic therapy has not been convincingly demonstrated, ing cultures and the problem of women coming late or not and prophylaxis may not be practical in most patient at all for prenatal care, other investigators developed Chapter 34 • Streptococcal Infections 703 strategies based on maternal risk factors alone. This led, in apy, with the duration depending on culture results and 1992, to the promulgation of two divergent sets ofrecom• clinical course. If the infant is asymptomatic and ;,,35 mendations proposed by the American Academy of Pedi• weeks' gestation, and the mother received intrapartum atrics (AAP) and by the American College of Obstetri• penicillin >4 hr (usually at least two doses), then no cians and Gynecologists (ACOG). The AAP guidelines evaluation or therapy is needed, but the infants should be stressed the use of third-trimester cultures of mothers and observed closely for at least 48 hr. If an asymptomatic recommended intrapartum prophylaxis for colonized infant is born to a mother receiving prophylaxis <4 hr mothers with certain risk factors. The ACOG guidelines (one dose), then a limited evaluation, including complete used similar criteria for initiation of antibiotic prophylaxis blood count with differential and , and obser• but did not depend on third-trimester cultures. The AAP vation ;,,48 hr are warranted. approach was more difficult and costly but limited anti• biotic use to about 5% of mothers. The ACOG approach This strategy represents a number of compromises. was logistically easier and eliminated the cost of antepar• While it promotes universal screening cultures, it allows tum cultures. However, it required that about 25% of for risk-factor management for situations in which cul• mothers be given antibiotics, increasing the likelihood of tures are not readily available or results are unknown. untoward drug reactions and raising the possibility of Delaying the screening culture to 35-37 weeks' gestation increased antibiotic resistance in other bacteria. Consider• enhances the reliability of both positive and negative able debate ensued, resulting in little acceptance of either predictive values. Although most mothers who begin labor protocol. at <37 weeks would be given prophylaxis, this represents In 1996, the CDC, supported by experts from the only about 10% of deliveries, but group B streptococcal ACOG, AAP, and other professional organization, devel• disease tends to be more severe in this age group. Peni• oped a set of guidelines that combined the essential fea• cillin was selected as the antibiotic of choice in order to tures of both ACOG and AAP approaches. For further narrow the antibiotic spectrum and reduce the use of background and details of the new guidelines, the reader ampicillin or cephalosporins. Clindamycin or erythro• should review the CDC consensus report,(l62) the ACOG mycin are alternatives for penicillin-allergic mothers, but policy statement,(163) and the revised AAP guidelines.(l64) these drugs have not been studied systematically in this The combined approach has the following key elements: setting. Physicians remain free to use other antibiotics as indicated by clinical considerations that go beyond the 1. Intrapartum penicillin should be given to mothers guidelines. Although the 1996 guidelines were developed who have had a previous infant with invasive group B on the basis of a number of prospective studies, these streptococcal disease; to mothers who develop group B guidelines have not been subjected to any large-scale streptococcal bacteruria during the current pregnancy; controlled experience. and to those delivering at <37 weeks' gestation. Several reports have called attention to instances of 2. All pregnant women should be screened at 35- failure of intrapartum antibiotics to prevent group B strep• 37 weeks' gestation by obtaining vaginal and anorectal tococcal sepsis.(I65.1 66) In a retrospective series, Ascher et swabs processed with selective culture methods. If the al.(I66) identified 18 (out of 96) infants who developed screening culture is negative for group B streptococci, sepsis despite antepartum maternal antibiotics. However, then no intrapartum prophylaxis is needed. If the screen• the median number of antepartum antibiotic doses was ing culture is positive, intrapartum penicillin should be one (range 1-21), with a median time of 4 hr prior to offered. If no culture was done or if results are not known delivery. Neither the 1992 AAP nor ACOG guidelines was at the time of labor, prophylaxis should be given if the specifically followed. These observations are important, mother has a temperature;" 100.4 OF (;"38.0°C) or if mem• because they demonstrate that intrapartum antibiotics are branes are ruptured ;" 18 hr. unlikely to prevent all neonatal infections, as originally 3. The management of infants whose mothers re• cautioned by Boyer and Gotoff.(I61) It is also apparent that ceive intrapartum prophylaxis remains empiric, and rec• most of the "prophylaxis" failures were actually failures ommendations are not meant to be restrictive. If the infant to eradicate infections that were already well established shows signs or symptoms of sepsis, or if the infant is born by the time of delivery. at <35 weeks' gestation, the physician should do a full Prevention of neonatal infections by vaginal chI or• diagnostic evaluation with a complete blood count with hexadine disinfection during labor has also been investi• differential and cultures of blood and cerebrospinal fluid if gated.(I67) A reduction in transmission of group B strep• indicated; this should followed by empiric antibiotic ther- tococci from mother to infant has been demonstrated, but 704 Part II • Acute Bacterial Infections

numbers have been too small to assess an effect of preven• virtually impossible. Although a single broadly protective tion of infections. This approach might reduce the number M protein epitope does not appear to exist,(53) certain of infections that develop as a result of colonization of conserved epitopes have been found to be common among infants during delivery, but as with intrapartum anti• different M types. This feature has been used to make oral biotics, it should not be expected to affect infections that synthetic peptide vaccines (coupled to a cholera toxin are already established in utero. Most authorities recog• subunit adjuvant) that induce mucosal immunity in mice nize inherent limitations in chemoprophylactic approaches and reduce the effects of nasopharyngeal challenge of to prevention. Although there has been considerable pro• streptococci.(53,173) Another approach uses cloned M pro• gress in developing vaccines against group B strep• tein expressed in live attenuated strains of Salmonella tococci,068) it is not known if vaccine immunity will given orally to mice.(174) Dale et at. (175) have constructed be protective to the immature fetus, which normally re• a recombinant tetravalent vaccine containing M protein ceives a minimal amount of maternal antibody. Thus, epitopes that are protective (opsonic) but not tissue cross• chemoprophylactic strategies may serve a purpose well reactive. A second generation of this vaccine has been into the future. coupled to Escherichia coli labile toxin and given to mice intranasally.(l76) The possibility of inducing antibodies that cross-react with human tissue is of obvious concern 9.5. Passive Immune Prophylaxis against but could be minimized by the oral route of administration Streptococcal Infections and by the identification and selection of vaccine epitopes The administration of gamma globulin has been em• that have no homology with host proteins.(l42) ployed for prevention of various bacterial infections in Group B polysaccharide vaccines have been under immunodeficient patients. The spectrum of host defense investigation for over a decade. The goal of the vaccine abnormalities that may benefit from this approach now approach is to immunize women in order to induce anti• includes patients with hypogammaglobulinemias, IgG body that will later be capable of protecting the fetus subclass deficiencies, malignancy and immunosuppres• against early-onset disease and perhaps afford protection sion, severe bums, bone marrow transplantation, and HIV for several months against late-onset disease. Ideally, a infection.(169) Immunoglobulin preparations suitable for vaccine should induce antibodies of the IgG class and be intravenous administration are still under investigation for effective against all four major serotypes; it should be safe prevention and adjunctive therapy of group B streptococ• for administration to pregnant women and it should in• cal disease in neonates, but implementation of this ap• duce long-lived immunity if administered prior to preg• proach is hampered by logistical factors and the relative nancy. One experimental vaccine consisting of purified infrequency of streptococcal infections. A specialized type III polysaccharide has been tested in a small number hyperimmune globulin has been prepared from plasma of women at about 30 weeks of gestation.(177) Results donors immunized with pneumococcal and H. injiuenzae indicated that some antibody could be induced in about type b, and meningococcal vaccines. This bacterial poly• 60% of mothers and that this antibody was predominantly saccharide immune globulin (BPIG) has been shown to be IgG with functional activity demonstrated in the infant's effective in reducing the number of pneumococcal and H. cord serum. The immunogenicity of group B polysac• injiuenzae type b infections in high-risk Apache and other charides has been significantly improved by coupling to Native American infant populations.(170) There is also tetanus toxoid. A tetravalent conjugate vaccine (types la, some evidence for the efficacy of BPIG in preventing Ib, II, and III) has been tested in a mouse immunization• pneumococcal otitis media in suburban middle-class in• neonatal challenge model. (168) Assuming the eventual de• fants.(l71) It should be noted that passive immunotherapy velopment of an appropriate vaccine, it will still be neces• was used for a short time with considerable success in the sary to carefully define the target population. There is yet treatment of pneumococcal pneumonia just prior to the little enthusiasm for administering vaccines to pregnant advent of penicillin. (172) women, because of liability issues, and it is possible that the target population would have to be broadened to include nonpregnant women of childbearing age. The 9.6. Immunization against Streptococcal Infections prospects for protecting the more premature fetus is un• A vaccine against rheumatic fever has been the holy certain, since only a minimal amount of maternally de• grail of many investigators over the years. The difficulties rived antibody is able to cross the placenta before the last involved are considerable and as yet only partially solved. trimester. Nevertheless, it would be reasonable to suggest The multitude of M protein types makes a simple vaccine that any degree of protection afforded the mother would Chapter 34 • Streptococcal Infections 705 indirectly affect the fetus. Here, a better understanding of tection. Fluoride mouth washes are probably of marginal the determinants of colonization and the mechanisms of value in communities with fluoridated water. They are not mucosal immunity is clearly needed. intended for children under 5 years of age, who may ingest Pneumococcal vaccines have been studied for nearly excessive amounts and be in danger of fluorosis. Profes• 80 years. Their history and current recommendations for sional application of topical fluoride may be helpful for use are summarized in Chapter 28. The current pneu• high-risk individuals and patients with active caries but is mococcal vaccine formulation, licensed in 1983, includes not currently recommended for routine use because of the purified capsular polysaccharides of 23 pneumococcal overall decline in caries incidence. serotypes most commonly associated with disease. The Sealing of dental pits and fissures with synthetic vaccine efficacy has been estimated at about 60% against resins has been done for over 15 years with marked suc• bacteremic infections in adults.(l78) The vaccine is vastly cess. Sealants do not add significant protection to initially underutilized, but considerable debate is still going on sound tooth surfaces.(181) Although application of sealants regarding its role in preventing adult pneumococcal dis• is not widely practiced, this approach is recommended for ease.(179.180) selected high-risk patients whose permanent molars have The current pneumococcal vaccine is not recom• erupted within the previous 2-3 years.(108) mended for children under 2 years of age, who respond The need for and effectiveness of dietary counseling poorly to bacterial polysaccharides in general. However, a aimed at reducing intake of sucrose has not been estab• new generation of protein-conjugated pneumococcal vac• lished but may be indicated for high-risk individuals. cines has been modeled after the spectacularly successful Avoiding prolonged use of baby bottles and bedtime bot• vaccines against H. injluenzae type b (Hib )(147.148) (see tle propping may prevent "nursing caries," but there is Chapter 16). These vaccines contain polysaccharides se• not much evidence to support the notion that counseling lected from among the seven or so most common types in changes this practice in many families. Traditional brush• childhood infections (types 1 or 4, 6B, 9V, 14, 18C, 19F, ing and flossing has little or no effect on caries prevention, and 23F)(l20) coupled to either diphtheria toxin mutant except as a method of applying fluoride in the form of a protein (Lederle-Praxis) or meningococcal outer mem• dentifrice. Professional cleaning (dental prophylaxis) brane protein complex (Merck & Co.), similar to the does not prevent caries, although it may be useful for licensed Hib vaccines. Another vaccine currently under removing stains or calculus. investigation is derived from a pneumococcal surface Vaccines against dental caries, based on antigens protein (PspA) that has been shown to be immunogenic derived from S. mutans, have been under investigation for and protective in anima1s.(77) A phase I trial of a candidate a number of years. (182.183) Several candidate vaccines have PspA vaccine for humans is currently in progress. been successful in preventing caries in experimental ani• mals. Among these are the adhesin complex (Ag IIII) involved in attachment of the bacteria to dental surfaces 9.7. Prevention of Dental Caries and the glycosyltransferases that synthesize adhesive glu• Conventional approaches to caries prevention have can from sucrose. Novel strategies have been developed been succinctly reviewed by the Lewis et al. and the for delivery of candidate vaccines, including use of aviru• Canadian Task Force on the Periodic Health Examina• lent Salmonella genetically engineered to express S. mu• tion.(108) Primary prevention includes fluoride, fissure tans vaccine antigens, and attachment to the nontoxic but sealants, dietary counseling, oral hygiene, and identifica• immunogenic B subunit of cholera toxin. Limited studies tion and care of individuals at high risk of developing have shown that some oral vaccines induce salivary IgA dental caries. Patients at greatest risk are those with bu• antibody responses in humans, but long-term evaluations limia, Sjogren's syndrome, chemotherapy, radiation ther• of efficacy have not been done. The major reason is that apy, or use of drugs that reduce saliva flow over long dental caries is not a life-threatening disease, and potential periods. benefits must clearly outweigh even theoretical concerns Fluoridation of drinking water at levels of 0.7-1.2 of safety. ppm remains the single-most effective method of prevent• ing coronal and root caries. In localities without natural or artificial fluoridation (fluoride <0.3 ppm), supplemental 10. Unresolved Problems fluoride may be given by prescription for persons >3 years of age and for those at high risk for dental caries. Despite the availability of antibiotics, the diagnosis Fluoride-containing toothpastes provide additional pro- and treatment of group A streptococcal pharyngitis con- 706 Part II • Acute Bacterial Infections

tinue to pose problems for the clinician. The distinction saccharides is not understood, and the role of systemic and between infection and carrier state is frequently blurred. secretory antibodies has yet to be fully explored. The new rapid diagnostic tests make it possible to treat The unanswered questions apparent from the discus• promptly and reduce clinical symptoms, but it is unlikely sions in this chapter remain: How do streptococci cause that changes in clinical practice have influenced the recent disease, and why do some individuals become infected resurgence of acute rheumatic fever or of severe invasive while others do not? Major virulence factors, such as streptococcal disease and toxic shock. Further study of exotoxins, enzymes, M proteins, and polysaccharide cap• epidemiological factors, pathogenic mechanisms, and sules, have been identified, but the pathophysiological host response is clearly needed. Poststreptococcal reac• mechanisms by which they interact with the host remain tive arthritis and its less certain relationship with cardiac uncertain and do not completely explain the disease pro• sequelae continues to present a clinical dilemma for clini• cesses. The determinants of colonization, the defenses of cians. Group A streptococci, along with staphylococci, the host at the mucosal level, and the development of local have been suggested as an etiology for Kawasaki disease, and systemic immunity are not well understood. More a vasculitis syndrome that occurs mainly in children.(184) needs to be learned to facilitate the development of effec• It is hypothesized that staphylococcal toxin TSST-I or tive vaccines and implement other preventive measures. streptococcal exotoxins act as "superantigens" and cause aberrant amplification of certain T-cell lines implicated in ACKNOWLEDGMENTS the disease. Group A streptococcal superantigens also The author thanks Gregory Valainis and Richard Penne• seem to playa role in streptococcal toxic shock, but effects baker, Division of Medical Education, Spartanburg Re• are manifested by a pattern of depletion of VI3 T-cell gional Medical Center, for review of this chapter. Data for subsets.(lBS) Proof of this, however, would probably re• Figs. 2 and 3 were kindly supplied by Caroline Breese quire showing that a particular antigen induced specific Hall, University of Rochester, New York. T-cell subsets to expand and subsequently be depleted by apoptosis (a process of programmed cell death). Group B streptococci remain the most common cause of serious bacterial disease in newborn infants in 11. References many Western countries. Despite similar maternal coloni• zation rates and presumably similar risk of exposure, the I. Quinn, R., Streptococcal infections, in: Bacterial Infections in Humans, 1st ed. (A. S. Evans and H. A. Feldman, eds.), pp. 525- disease is infrequent in some areas of Europe and Asia. 552, Plenum Press, New York, 1982. The reasons for this are not clear but could be of consider• 2. Stollerman, G. H., Variation in group A streptococci and the able practical importance. Methods for intrapartum anti• prevalence of rheumatic fever: A half-century vigil, Ann. Intern. biotic prophylaxis have been established but remain to be Med. 118:467-469 (1993). implemented on a wide scale. Meanwhile, we still have 3. Veasy, L. G., Tani, L. Y, and Hill, H. R., Persistence of acute rheumatic fever in the intermountain area of the United States, 1. little understanding of the local and systemic defense Pediatr. 124:9-16 (1994). mechanisms required to prevent infection by this usually 4. Stevens, D. L., Invasive group A Streptococcus infections, Clin. benign organism. Other streptococci, particularly oral and Infect. Dis. 14:2-13 (1992). enteric species, are constant companions that cause dis• 5. 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