Streptococcus pyogenes, other Streptococci, and Enterococcus

Streptococcus pneumoniae

Structure

Both S pyogenes and S pneumoniae are Gram-positive cocci, nonmotile, and nonsporulating; they usually require complex culture media. S pyogenes characteristically is a round-to-ovoid coccus 0.6-1.0 μm in diameter (Fig. 13-1). They divide in one plane and thus occur in pairs, or (especially in liquid media or clinical material) in chains of varying lengths. S pneumoniae appears as a 0.5-1.25 μm diplococcus, typically described as lancet-shaped but sometimes difficult to distinguish morphologically from other streptococci. Streptococcal cultures older than the logarithmic phase, which is the most active growth period of a culture, may lose their Gram-positive staining characteristics.

Figure 13-1

Morphology of the streptococci in comparison with staphylococci. Streptococci divide in a single plane and tend not to separate, causing chain formation. Capsules are antiphagocytic.

Unlike Staphylococcus (Chapter 12), all streptococci lack the enzyme catalase. Most are facultative anaerobes but some are obligate anaerobes. Streptococci often have a mucoid or smooth colonial morphology, and S pneumoniae colonies exhibit a central depression caused by rapid partial autolysis. As S pneumoniae colonies age, viability is lost during fermentative growth in the absence of catalase and peroxidase because of the accumulation of peroxide. Some group B and D streptococci produce pigment. Recently, nutritionally deficient streptococci (also known as wall-deficient, L form, thiol-requiring, satelliting, or pyridoxal-dependent) have been recovered from a variety of clinical sources, including blood, abscesses, and oral and urethral ulcers. These variants demonstrate bizarre pleomorphism microscopically and do not grow on routine subculture.

Antigenic Types

The cell wall structure of group A streptococci is among the most studied of any bacteria (Fig. 13-2). The cell wall is composed of repeating units of N-acetylglucosamine and N-acetylmuramic acid, the standard peptidoglycan. For decades, the definitive identification of streptococci has rested on the serologic reactivity of cell wall polysaccharide antigens originally delineated by Rebecca Lancefield. Eighteen group-specific antigens were established. The group A polysaccharide is a polymer of N-acetylglucosamine and rhamnose. Some group antigens are shared by more than one species; no Lancefield group antigen has been identified for S pneumoniae or for some other α- or γ-streptococci. With advances in serologic methods, other streptococci have been shown to possess several established group antigens.

Figure 13-2

Cell surface structure of S pyogenes and extracellular substances.

The cell wall also consists of several structural proteins (Figure 13-2). In group A streptococci, the R and T proteins may serve as epidemiologic markers, but the M proteins are clearly virulence factors associated with resistance to phagocytosis. More than 50 types of S pyogenes M proteins have been identified on the basis of antigenic specificity. Both the M proteins and lipoteichoic acid are supported externally to the cell wall on fimbriae, and the lipoteichoic acid, in particular, appears to mediate bacterial attachment to host epithelial cells. M protein, peptidoglycan, N-acetylglucosamine, and group-specific carbohydrate portions of the cell wall have antigenic epitopes similar in size and charge to those of mammalian muscle and connective tissue. Recently emerging strains of increased virulence are distinctly mucoid, rich in M protein and highly encapsulated.

The capsule of S pyogenes is composed of hyaluronic acid, which is chemically similar to that of host connective tissue and is therefore nonantigenic. In contrast, the antigenically reactive and chemically distinct capsular polysaccharide of S pneumoniae allows the single species to be separated into more than 80 serotypes. The antiphagocytic S pneumoniae capsule is the most clearly understood virulence factor of these organisms; type 3 S pneumoniae , which produces copious quantities of capsular material, are the most virulent. Unencapsulated S pneumoniae are avirulent. The polysaccharide capsule in S agalactiae allows differentiation into types Ia, Ib, Ic, II and III.

Finally, the cytoplasmic membrane of S pyogenes has antigens similar to those of human cardiac, skeletal, and smooth muscle, heart valve fibroblasts, and neuronal tissues, resulting in a molecular mimicry.

Extracellular Growth Products

The importance of the interaction of streptococcal products with mammalian blood and tissue components is becoming widely recognized. The soluble extracellular growth products or toxins of the streptococci, especially of S pyogenes (seeFig. 13-2), have been studied intensely. Streptolysin S is an oxygen-stable cytolysin; Streptolysin O is a reversibly oxygen-labile cytolysin. Both are leukotoxic, as is NADase. Hyaluronidase (spreading factor) can digest host connective tissue hyaluronic acid as well as the organism's own capsule. Streptokinases participate in fibrin lysis. Streptodornases A-D possess deoxyribonuclease activity; B and D possess ribonuclease activity as well. Protease activity similar to that in Staph aureus has been shown in strains causing soft tissue necrosis or toxic shock syndrome. This large repertoire of products may be important in the pathogenesis of S pyogenes by enhancing virulence; however, antibodies to these products appear not to protect the host even though they have diagnostic importance.

Three pyrogenic exotoxins of S pyogenes (SPEs) are recognized: types A, B, C. These toxins act as superantigens by a mechanism similar to those described for staphylococci, not requiring processing by antigen presenting cells. Rather, they stimulate T cells by binding class II MHC molecules directly and nonspecifically. With superantigens about 20% of T cells may be stimulated (vs 1/10,000 T cells stimulated by conventional antigens) resulting in massive detrimental cytokine release. When S pyogenes is lysogenized by certain bacteriophages, the SPEs A or C are produced; nonlysogenized strains are atoxic. SPE B is encoded by the bacterial chromosome. Re-emergence in the late 1980's of these exotoxin-producing strains has been associated with a toxic shock-like syndrome similar in pathogenesis and manifestation to staphylococcal toxic shock syndrome (Ch.12) and other forms of invasive disease associated with severe tissue destruction. SPE's have also been identified from non group A streptococci (groups B, C, F. G) in association with the toxic shock-like syndrome.

Virulence factors in the other streptococcal species, including the enterococci, are less well identified. In group B streptococci, carbohydrate surface antigens associated with antiphagocytosis have been identified, as has neuraminidase, which may play a role in pathogenesis. Among the viridans streptococci, production of the exopolysaccharide (glycocalyx) is associated with the ability to adhere to the cardiac valves and to form vegetations on the valve leaflets.

Streptococcus pyogenes and Streptococcus pneumoniae

Streptococci vary widely in pathogenic potential. Despite the remarkable array of cell-associated and extracellular products previously described (Fig.13- 2), no clear scheme of pathogenesis has been worked out. S pneumoniae and, to a lesser extent, S pyogenes are part of the normal human nasopharyngeal flora. Their numbers are usually limited by competition from the nasopharyngeal microbial ecosystem and by nonspecific host defense mechanisms, but failure of these mechanisms can result in disease. More often disease results from the acquisition of a new strain following alteration of the normal flora. S pyogenes causes inflammatory purulent lesions at the portal of entry, often the upper respiratory tract or the skin. Some strains of streptococci show a predilection for the respiratory tract; others, for the skin. Generally, streptococcal isolates from the pharynx and respiratory tract do not cause skin infections.

Invasion of other portions of the upper or lower respiratory tracts results in infections of the middle ear (otitis media), sinuses (sinusitis), or lungs (pneumonia). In addition, meningitis can occur by direct extension of infection from the middle ear or sinuses to the meninges or by way of bloodstream invasion from the pulmonary focus. Bacteremia can also result in infection of bones (osteomyelitis) or joints (arthritis).

S pyogenes (a group A streptococcus) is the leading cause of uncomplicated bacterial pharyngitis and tonsillitis (Fig. 13-3). Indeed, only group A streptococci are sought routinely in cases of pharyngitis, although groups B, C, and G are sometimes identified. S pyogenes infections can also result in sinusitis, otitis, mastoiditis, pneumonia with empyema, joint or bone infections, necrotizing fasciitis or myositis, and, more infrequently, in meningitis or endocarditis. S pyogenes infections of the skin can be superficial (impetigo) or deep (cellulitis). Although scarlet fever was formerly a severe complication of streptococcal infection, because of antibiotic therapy it is now little more than streptococcal pharyngitis accompanied by rash. Similarly, erysipelas, a form of cellulitis accompanied by fever and systemic toxicity, is less common today. There has, however, been an apparent recent increase in variety, severity and sequelae of S pyogenes infections. Because cases of streptococcal disease are not reported to national disease clearinghouses in the US, absolute numbers are not available. However, the recent resurgence of severe invasive infections has prompted descriptions of “flesh eating bacteria” in the news media. There has been no major change in susceptibility of S pyogenes to commonly used antibiotics but rather in the strain variations described above (antigenic types and extracellular growth products). However, a complete explanation for the decline and resurgence is not yet available.

Figure 13-3

Pathogenesis of S pyogenes infections.

The capsule of S pneumoniae renders it resistant to phagocytosis. The ability to evade this important host defense mechanism allows S pneumoniae to survive, multiply, and spread to various organs (Fig.13-4). The cell wall of S pneumoniae contains teichoic acid. The inflammatory response induced by Gram-positive cell walls differs from that induced by the endotoxin of Gram-negative organisms, but does include recruitment of polymorphonuclear neutrophils, changes in permeability and perfusion, cytokine release, and stimulation of platelet-activating factor. The role of other S pneumoniae moieties in virulence is less clear: protein A, pneumolysin, and peptide permeases. S pneumoniae is the leading cause of bacterial pneumonia beyond the neonatal period. Pleural effusion is the most common and empyema (pus in the pleural space) one of the most serious complications of S pneumoniae . This organism is also the most common cause of sinusitis, acute bacterial otitis media, and conjunctivitis beyond early childhood. Dissemination from a respiratory focus results in serious disease: outpatient bacteremia in children, meningitis, occasionally acute septic arthritis and bone infections in patients with sickle cell disease and, more rarely, peritonitis (especially in patients with nephrotic syndrome) or endocarditis.

Figure 13-4

Pathogenesis of S pneumoniae infections.

Other Streptococcal Species

Clinical

It is not usually possible to diagnose streptococcal pharyngitis or tonsillitis on clinical grounds alone. Accurate differentiation from viral pharyngitis is difficult even for the experienced clinician, and therefore the use of bacteriologic methods is essential. However, distinguishing acute streptococcal pharyngitis from the carrier state may be difficult. When documented streptococcal pharyngitis is accompanied by an erythematous punctiform rash (Fig.13-4), the diagnosis of scarlet fever can be made. With streptococcal toxic shock syndrome, unlike staphylococcal toxic shock syndrome where the organism is elusive, there is often a focal infection or bacteremia. Criteria for diagnosis of streptococcal toxic shock syndrome include hypotension and shock, isolation of S pyogenes , as well as 2 or more of the following: ARDS, renal impairment, liver abnormality, coagulopathy, rash with desquamating soft tissue necrosis. The invasive, potentially fatal S pyogenes infections require early recognition, definitive diagnosis, and early aggressive treatment.

Rheumatic fever is a late sequela of pharyngitis and is marked by fever, polyarthritis, and carditis. A combination of clinical and laboratory criteria (Table 13-2) is used in the diagnosis of acute rheumatic fever. Since the original Jones criteria were published in 1944, these have been modified (1955), revised (1965, 1984) and updated (1992). The other late sequela, acute glomerulonephritis, is preceded by pharyngitis or pyoderma; is characterized by fever, blood in the urine (hematuria), and edema; and is sometimes accompanied by hypertension and elevated blood urea nitrogen (azotemia). Pneumococcal pneumonia is a life-threatening disease, often characterized by edema and rapid lobar consolidation.

Table 13-2

Jones Diagnostic Criteria for Acute Rheumatic Fever ^a.

Specimens For Direct Examination And Culture

S pyogenes is usually isolated from throat cultures. In cases of cellulitis or erysipelas thought to be caused by S pyogenes , aspirates obtained from the advancing edge of the lesion may be diagnostic. S pneumoniae is usually isolated from sputum or blood. Precise streptococcal identification is based on the Gram stain and on biochemical properties, as well as on serologic characteristics when group antigens are present.Table 13-3shows biochemical tests that provide sensitive group-specific characteristics permitting presumptive identification of Gram-positive, catalase-negative cocci.

Table 13-3

Characteristics for the Presumptive Indentification of Streptococci of Human Clinical Importance.

Identification

Hemolysis should not be used as a stringent identification criterion. Bacitracin susceptibility is a widely used screening method for presumptive identification of S pyogenes; however, some S pyogenes are resistant to bacitracin (up to 10%) and some group C and G streptococci (about 3-5%) are susceptible to bacitracin. Some of the group B streptococci also may be bacitracin sensitive, but are presumptively identified by their properties of hippurate hydrolysis and CAMP positivity. S pneumoniae can be separated from other α-hemolytic streptococci on the basis of sensitivity to surfactants, such as bile or optochin (ethylhydrocupreine hydrochloride). These agents activate autolytic enzymes in the organisms that hydrolyze peptidoglycan.

In many instances, presumptive identification is not carried further. Serologic grouping has not been performed as often as it might be because of the lack of available methods and the practical constraints of time and cost; however, only serologic methods, as listed inTable 13-4, provide definitive identification of the streptococci. The Lancefield capillary precipitation test is the classical serologic method. S pneumoniae, which lacks a demonstrable group antigen by the Lancefield test, is conventionally identified by the quellung or capsular swelling test that employs type-specific anticapsular antibody. Inspection of Gram-stained sputum remains a reliable predictor for initial antibiotic therapy in community-acquired pneumonia.

Table 13-4

Methods of Serogrouping Streptococci.

New methods for serogrouping that show sensitivity and specificity now are being explored. Organisms from throat swabs, incubated for only a few hours in broth, can be examined for the presence of S pyogenes using the direct fluorescent antibody or enzyme-linked immunosorbent technique. Additional rapid antigen detection systems for the group carbohydrate have become increasingly popular. However, the sensitivity (70-90%) of these currently available rapid tests for group A streptococcal carbohydrate does not allow exclusion of streptococcal pharyngitis without conventional throat culture (sensitivity of a single throat culture is 90-99%). A third generation assay, the optical immunoassay, is currently being evaluated. S pneumoniae can be identified rapidly by counterimmuno-electrophoresis, a modification of the gel precipitin method. The coagglutination test, described in Ch.12, is a more sensitive modification of the conventional direct bacterial agglutination test. The Fc portion of group-specific antibody binds to the protein A of dead staphylococci, leaving the Fab portion free to react with specific streptococcal antigen. The attachment of antibody to other carrier particles in suspension (for example, latex) also is used. The fact that whole streptococcal cells can be used in recently developed methods circumvents the difficulties involved in extracting components that retain appropriate antigenic reactivity. These newer serogrouping methods should make it more practical to identify not only β-hemolytic isolates from the blood or normally sterile sites, but also α-and nonhemolytic strains. It has become increasingly important to identify more of these strains to avoid simply misclassifying them as contaminants. Such information will expand our understanding of the importance of non-group-A streptococci.

Serologic Titers

Antibodies to some of the extracellular growth products of the streptococci are not protective but can be used in diagnosis. The antistreptolysin O (ASO) titer which peak 2-4 wks after acute infection and anti-NADase titers (which peaks 6-8 weeks after acute infection) are more commonly elevated after pharyngeal infections than after skin infections. In contrast, antihyaluronidase is elevated after skin infections, and anti-DNase B rises after both pharyngeal and skin infections. Titers observed during late sequelae (acute rheumatic fever and acute glomerulonephritis) reflect the site of primary infection. Although it is not as well known as the ASO test, the anti-DNase B test appears superior because high-titer antibody is detected following skin and pharyngeal infections and during the late sequelae. Those titers should be interpreted in terms of the age of the patient and geographic locale.

Although not used in diagnosis, bacteriocin production and phage typing of streptococci are employed in research and epidemiologic studies.

Antibiotic Treatment

Penicillin remains the drug of choice for S pyogenes . It is safe, inexpensive, and of narrow spectrum, and there is no direct or indirect evidence of loss of efficacy. Prior to the 1990's, S pneumoniae was also uniformly sensitive to penicillin but a recent abrupt shift in the usefulness of penicillin has occurred. The group D enterococci are resistant to penicillins, including penicillinase-resistant penicillins such as methicillin, nafcillin, dicloxacillin, and oxacillin, and are becoming increasingly resistant to many other antibiotics. Group B streptococci are often resistant to tetracycline but remain sensitive to the clinically achievable blood levels of penicillin, even though they have penicillin minimal inhibitory concentrations (MIC) considerably higher than those of S pyogenes . Although the duration of penicillin therapy varies with the degree of invasiveness, streptococcal pharyngitis is generally adequately treated with 10 days of antibiotic therapy, and pneumococcal pneumonia with 7-14 days. If penicillin allergy occurs, an alternative drug for treating pharyngitis is erythromycin, although sporadic erythromycin and tetracycline resistance has been reported, leaving clindamycin or the newer macrolides as possible treatments. The most important goal of therapy in acute streptococcal pharyngitis is still to prevent rheumatic fever. However, therapy also hastens clinical recovery, avoids suppurative complications and renders the patient non-infectious for others. In addition to antibiotics, the patient with S pyogenes myositis or necrotizing fasciitis requires surgical debridement. Lifelong prophylaxis against recurrences of rheumatic fever is achieved with long-acting penicillin or erythromycin. Sulfonamides will not eradicate the streptococcus and thus are not acceptable therapy for streptococcal pharyngitis, but sulfadiazine is effective for preventing recurrent attacks of rheumatic fever. Additional prophylactic coverage before some dental and surgical procedures is necessary in the presence of rheumatic heart disease or prosthetic heart valves. Although streptococcal pharyngitis is usually a benign, self-limited disease, therapy is important to prevent rheumatic fever. There is no convincing evidence that antibiotic therapy prevents glomerulonephritis. Disconcertingly, some patients in recent outbreaks of acute rheumatic fever do not give a history of preceding pharyngitis.

Methods of treating the asymptomatic pharyngeal carrier of S pyogenes remain controversial. Recent evidence suggests that up to 20% of children and young adults are carriers, the carrier state involves no risk to the carrier or to others, and it is frequently difficult to eradicate despite the exquisite sensitivity of the organism to penicillin in vitro. A similar failure of antibiotic therapy to eradicate nasopharyngeal carriage or to prevent reinfection with S pneumoniae also occurs.

Although antibiotic resistance in S pneumoniae is common in many parts of the world, in the United States such strains previously had a geographically limited focus. Recent widespread emergence of S pneumoniae resistant to penicillin and other antibiotics has become a microbial threat in the United States as well. Even cefotaxime and ceftriaxone resistance has been documented. Isolates must be carefully screened for susceptibility by oxacillin disc testing, with definitive MIC determination by the E test (A B Biodisk NA, Piscataway, NJ), a convenient and reliable method for detection of resistance to penicillin and extended spectrum cephalosporins.

It is inappropriate to universally treat of pregnant women who are carriers of group B streptococci, or their colonized neonates, for several reasons: the high carrier rate; cost; the associated high risk of penicillin hypersensitivity; the potential increase in infections with penicillin-resistant organisms; the difficulty in altering colonization of women (even when their sexual partners were also treated); and the low risk of neonatal disease. The controversy continues despite recent recommendations for universal screening of preg nant women and selective intrapartum chemoprophylaxis for screen-positive mothers with preterm labor, premature or prolonged rupture of membranes, fever in labor, multiple births or previous infants with group B streptococcal disease.

Clearly, penicillin has reduced the severe morbidity and mortality associated with S pneumoniae . The emergence of resistance has now forced re-evaluation of empiric therapy. Clinicians must report clusters of S pneumoniae infection and be aware of local patterns of resistance. Penicillin susceptible organisms show MICs ≤ 0.06 mg/ml, intermediate strains 0.1-1.0 mg/ml and high level resistant strains ≥ 2 mg/ml. For nonmeningeal infection by intermediate strains, parenteral penicillin at high dose can probably be used since the mechanism of resistance involves alteration in penicillin binding proteins (PBP) and saturation. For meningeal infection with intermediate strains or any infection by high level resistant strains only ceftriaxone and cefotaxime retain sufficient activity. Resistance even to these extended spectrum cephalosporins was first reported for the US in 1991. At this writing only vancomycin remains uniformly effective but as discussed below, its use incurs potential for selection of vancomycin resistant enterococci (VRE) or risk of transferring vancomycin resistance from enterococci to S pneumoniae .

Currently, no single agent is reliably bactericidal against enterococci. Serious infections with group D enterococci often require a classic synergistic regime combining penicillin or ampicillin with an aminoglycoside, designed to weaken the cell wall with the β-lactam and facilitate entry of the bacteriocidal aminoglycoside. Other β-lactam drugs with good activity against enterococci include piperacillin and imipenem. An alternate drug of choice is vancomycin, but vancomycin-resistant strains of enterococci have been isolated. Nosocomial acquisition of these resistant organisms is of grave concern.

This antibiotic resistance among the streptococci/enterococci is an increasing problem. Studies show that in vitro exchange of resistant DNA can occur in conjugation via plasmids and transposons, or in transduction with bacteriophages. The mechanisms involved in the in vivo genetic exchange are not clearly defined. Evidence is accumulating that other streptococci may be the important donors of resistance markers. Transposon transfer is thought to be the most likely mechanism in S pneumoniae , although point mutations also occur. In the setting of heavy β-lactam use, selective pressure is important in emergence of resistant strains. The first penicillin-resistant S pneumoniae were reported in 1967 in Australia and in 1974 in North America. In New Guinea, where the first penicillin-resistant strains were reported in 1971, one-third of S pneumoniae isolates from patients with severe pneumococcal disease were resistant by 1978. In Hungary in 1992, 69% of S pneumoniae isolates were penicillin resistant. This resistance is not β-lactamase mediated but due to alteration in PBP which results in decreased binding of penicillin by the organism, rendering the drug less effective and requiring higher concentrations for saturation. Some strains resistant to erythromycin or tetracycline also have been reported, as well as some multiply resistant strains. In South Africa, outbreaks of infection with strains of S pneumoniae resistant to β-lactam antibiotics (penicillins and cephalosporins) as well as to tetracycline, chloramphenicol, erythromycin, streptomycin, clindamycin, sulfonamides, and rifampin were reported in 1977. Although antibiotic resistance among S pneumoniae was infrequent in the United States, a major shift occurred from 1988 to 1990, resulting in the present situation of 15-25% of S pneumoniae intermediately or completely resistant to penicillin. Communities with “low prevalence” have 5-10% resistance. Single or multiply resistant strains are transmitted person to person, especially in settings of frequent salivary exchange, antibiotic use and hand-to-hand transmission (as in day care centers) or of crowding (corrections facilities, homeless shelters, nursing homes, military training groups). Control of the problem of emerging, antibiotic-resistant S pneumoniae is multifactorial: 1) surveillance for clusters of invasive disease, resistance and prevalent serotypes; 2) education of physicians and the public about antibiotic use (decrease unnecessary antibiotic use for obviously viral infections and decrease antibiotic prophylaxis for otitis by use of intermittent or expectant dosing or of non β-lactam based prophylaxissulfa. Use topical treatment for impetigo, and short course therapies and narrow spectrum antibiotics); 3) adherence to infection control strategies in day care centers; 4) aggressive promotion of the current 23-valent S pneumoniae vaccine and support of efforts to design a new vaccine effective in those <2 years of age, analogous to the eminently successful Haemophilus influenzae type B vaccine (see Ch. 30) where bacterial polysaccharide is conjugated to protein to elicit a T cell-dependent response.

Among the enterococci, resistance to a wide variety of common antibiotics has emerged, with some strains resistant to all currently available antibiotics. There is no clinically proven treatment effective against enterococci multiply resistant to lactams, aminoglycosides, and vancomycin. The emergence of such organisms poses a stunning management dilemma. Resistance among the enterococci can be either intrinsic or acquired (by de novo genetic mutation or acquisition of DNA from resistant organisms). Enterococcal resistance to lactams is also mediated by altered PBP as in pneumococci, allowing cell wall synthesis even in the presence of antibiotic, or much less commonly by β-lactamase. Resistance to aminoglycosides is mediated by decreased uptake or aminoglycoside modifying enzymes, and to vancomycin by decreased cell wall affinity for glycopeptide antibiotics. Further research into the mechanisms of resistance and new class(es) of antibiotics is essential.

A final concern about emerging resistance among the enterococci is the potential for genetic transfer of resistance genes to more virulent pathogens: Staph aureus , S pneumoniae and even Gram-negative organisms. So significant is this threat of emerging enterococcal resistance that the Centers for Disease Control and Prevention has issued a document addressing national guidelines. These include recommendations for 1) education of physicians and the public about the impact of vancomycin resistant enterococci (VRE), 2) vigilant surveillance for and detection of VRE, 3) strict enforcement of infection control strategies in hospitals, and 4) prudent vancomycin use or monotherapeutic use of extended spectrum cephalosporins. In a recent study of vancomycin use in US hospitals, use was about equally divided for treatment of a specific isolate, for prophylaxis, and for empiric coverage. The recommendations discourage vancomycin use for routine surgical prophylaxis, empiric prophylaxis in the patient with febrile neutropenia, the low birth weight infant or patients with vascular or peritoneal catheters, treatment of a single blood culture positive for coagulase-negative staphylococci, primary treatment of antibiotic-associated colitis, attempted eradication of colonization by methicillin-resistant Staph aureus (MRSA), or selective decontamination of the gastrointestinal tract.

Vaccination

As chemotherapeutic management becomes more difficult because of the threat of resistance, prevention becomes more important. With the introduction of antibiotics, previously successful pneumococcal vaccines fell into disuse. However, although prompt treatment with antibiotics has reduced the serious consequences of S pneumoniae infections (pre-antibiotic mortality rate of 30%), the disease incidence remains unchanged, and attention has been redirected to vaccines for S pneumoniae as well as for other streptococci. Pneumococcal vaccines (containing the pneumococcal polysaccharides of the most prevalent serotypes) have been licensed in several countries, including the United States. Initial use shows them to be useful and safe, but they remain under-utilized. The spectre of multidrug resistant S pneumoniae may provide a new incentive for their use. In 1983, the United States Food and Drug Administration licensed a vaccine containing 23 serotypes, representing coverage against nearly 89% of the pneumococcal isolates submitted to the CDC in the 1987-1988 National Surveillance Study. The population target of pneumococcal vaccines includes those at high risk for serious pneumococcal disease: the elderly (65 and older) and children (2 years of age and older) with sickle cell anemia, with an immunocompromised state (lymphoma, asplenia, myeloma, acquired immunodeficiency syndrome), with nephrotic syndrome, or with chronic cardiopulmonary disease. Vaccines for the other streptococci remain experimental.

Vaccine production for the streptococci presents several formidable problems. For both S pyogenes and S pneumoniae , a large number of serotypes must be included in effective vaccines since successful selection of a common epitope remains elusive. Continuing surveillance to determine prevalent serotypes is necessary to insure that the vaccine formulations remain appropriate. For S pyogenes , it is critical to determine rheumatogenic and nephritogenic strains to limit the required multivalency of the vaccines. Alternatively a newly described conserved portion of M protein is a distant goal. Toxicity has been associated with M protein preparations, but lack of immunogenicity in highly purified preparations of antigens is still a problem. With streptococcal vaccines, the potential risk of antigenic cross-reactivity with cardiac tissue and an associated increased risk of acute rheumatic fever must be appreciated.

In group B neonatal disease chemoprophylaxis does not appear as practical as vaccine control. Passive immunity in group B streptococcal neonatal infection appears protective. Polyvalent hyperimmune gamma globulin and human monoclonal IgM antibody which reacts with multiple serotypes are undergoing efficacy studies. Active immunization of pregnant women with undegraded sialic acid-containing polysaccharide group B antigens is another important aspect of control.

The streptococci are ubiquitous, and their significance in medicine is remarkable. Exciting advances are being made in diagnosis and in understanding the mechanisms of pathogenesis, as well as in control of these well-known organisms. Problems with antibiotic resistance must preclude complacency in dealing with these common pathogens.