Streptococal NVE

The nomenclature of the streptococci is complex. However, with respect to NVE, it is clinically useful to divide streptococci into the following categories [11,12,27,28] : (1) oral (or viridans group) streptococci; (2) S. bovis complex; (3) nutritionally variant streptococci; (4) S. pneumoniae; and (5) beta-hemolytic streptococci.

Oral (or Viridans Group) Streptococci

The oral (or viridans group) streptococci are a heterogeneous group of streptococci that constitute a vital part of the normal flora of the human upper respiratory tract, gastrointestinal tract, and female genital tract. Previously, when rheumatic heart disease was prevalent, viridans streptococci were the most common cause of NVE, accounting for as much as 60-80% of all cases of IE; their incidence over the last 20 years has since decreased [2,29,30]. Currently, viridans group streptococci are divided into the following groups [31] : S. mutans group, S. salivarius group, S anginosus group (previously S. milleri group [32]), S. sanguinis group, and S. mitis group. Although the taxonomy of these organisms will change, what is important for the clinician to understand is the diversity of pathogens that clinically and therapeutically behave as "viridans streptococci" and that there are species-specific variation in antibiotic sensitivities.

Antimicrobial susceptibility testing of the viridans streptococci by CLSI (NCCLS) criteria categorize these pathogens as penicillin-susceptible (MIC < 0.12 mg/L), or penicillin non-susceptible, which are further classified as either intermediate (MIC 0.25-2 mg/L) or high resistance (MIC > 4 mg/L) [33]. These microbiological laboratory criteria, however, are different than those used by the AHA, BSAC, and the European Society of Cardiology (ESC), which define penicillin-susceptible as a MIC < 0.1 mg/L, intermediate as MIC 0.1-0.5 mg/L, or high resistance as MIC >0.5 mg/L [8,11,12,27]. The rationale for this discrepancy is unclear [34], but establishing lower MIC thresholds to label a viridans streptococci as "intermediate" or "resistance" presumably errs on the side of clinical caution and ensures more aggressive antimicrobial intervention. The clinical criteria are used in the recommendations of antibiotic therapy.

Previously, it was felt that all oral streptococci were fully sensitive to penicillin [35]. Since the 1990s, however, these Streptococcus spp. have been displaying increasing resistance to penicillin and other P-lactam antimicrobial agents. In particular, the S. mitis group is commonly implicated, especially (although not exclusively) among neutropenic cancer patients, who are exposed to various therapeutic and prophylactic antibiotic regimens [36-41]. Frequently, these penicillin non-susceptible viridans group streptococci also show reduced susceptibility to cef-triaxone, erythromycin, and clindamycin [35,42-44]. Glycopeptide resistance, however, is uncommon [35,42,44,45]. As well, high-level aminoglycoside resistance among the viridans streptococci is uncommon, although if present, it is more commonly reported with streptomycin than with gentamicin [8,45,46]. Streptomycin-resistant isolates, however, can still demonstrate in vitro synergistic susceptibility to the combination of penicillin and gentam-icin; conversely, gentamicin-resistant isolates do not always demonstrate high-level streptomycin resistance [46]. As such, testing for resistance to these aminoglycosides for each viridans streptococcal isolate should be performed.

Antimicrobial susceptibility testing dictates not only which antibiotics may be used, but also assists in determining the duration of therapy. Early clinical studies found that when a total dose of 14-16 million units of penicillin was given alone for up to 2 weeks, the relapse rate was 15%; this rate decreased to < 1.5% with four weeks of therapy [47]. Experimental evidence of the combination of penicillin with an aminogly-coside demonstrated more rapid eradication of streptococci from IE vegetations, as assessed by bacterial counts and relapse in animal models after termination of therapy [46]. Clinical studies of the two-week combination regimen demonstrated a relapse rate of 2% [48]. However, the patient population in these studies excluded those with shock or metastatic septic foci. Therefore, for viridans streptococci that are penicillin- and aminoglycoside-sensitive, a two-week treatment regimen may be considered, provided that appropriate conditions for short-course therapy are fulfilled. These conditions are outlined in Table 9.2.

The S. anginosus (or "S. milleri") group has a propensity to form abscesses, as well as to cause hematogenously disseminated infection [49,50]. More specifically, however, it appears that S. constellatus and S. intermedius of this group are more commonly associated with abscess

Table 9.2. Conditions for Two-Week Combination Therapy for PenicillinSensitive and Aminoglycoside-Sensitive Streptococcal Endocarditis

1. Penicillin-sensitive oral (or viridans group) streptococcus or S. bovis (penicillin MIC <0.1 |g/mL)

2. Native valve IE

3. No cardiac complications (e.g., intra-cardiac abscess, heart failure, aortic insufficiency, conduction abnormalities)

4. No extra-cardiac complications (e.g., septic embolic foci)

5. No vegetation >5 mm in diameter on echocardiography

6. Clinical response within 7 days:there should be resolution of fever,the patient should feel well, and the appetite should return formation, whereas S. anginosus is more commonly associated with IE [51]. Furthermore, it appears that IE due to the S. anginosus group, and S. anginosus in particular, may be associated with a higher mortality rate than IE due to other viridans streptococci [51]. As such, the duration of antimicrobial therapy for NVE caused by the S. anginosus group may need to be longer than that for NVE caused by other viri-dans streptococci [52].

The prevalence of penicillin non-susceptible viridans group streptococci has been increasing worldwide, with rates as high as 30-45% reported [36,40,43,53]. The mechanism of action appears to be alterations in penicillin-binding proteins [54]. The clinical significance is as expected, with increased morbidity and mortality reported among patients infected by these pathogens [37,55,56]. The degree of penicillin resistance (i.e., intermediate versus high) affects the antibiotic regimen selected, as well as the duration of therapy. The antibiotic regimens for the treatment of viridans streptococcal IE are provided in Table 9.3.

Table 9.3. Antibiotic Treatment for IE Due to Viridans Group Streptococci and S. bovis complex

Category

First-line

Duration

Second-line

Duration

Comments

Penicillin-sensitive

Penicillin G12-

4 weeks

Continuous infusion or q4h; BSAC

(MIC <0.1 mg/L)

18 million units/

recommends 10-20 million

day IV

units/day IV (i.e., 2-3 x 105

U/kg)

Ceftriaxone 2 g /

4 weeks

day IV

Penicillin G

2 weeks

See Table 9.2 for indications for

(above dose)+

2-week therapy.Gentamicin can

gentamicin 3 mg/

be given as once daily dosing;

kg/day IV

when 3 divided daily dosing is

used, aim for peak concentration

Ceftriaxone

2 weeks

of 3-4 |g/mL and trough

(above dose) +

concentration <1 |g/mL

gentamicin 3 mg/

kg/day IV

Vancomycin 30 mg/

4 weeks

Recommended only for P-lactam

kg/day IV q12h

intolerance; aim for peak

concentration of 30-45 |g/mL

1-h post infusion and trough

concentration of 10-15 |g/mL.

Vancomycin (above

2 weeks

Recommended by BSAC, not by

dose) + gentamicin

AHA

3 mg/kg/day IV

Relatively penicillin-

Penicillin G 24 million

2 weeks combined

Continuous infusion or q4h; BSAC

resistant (MIC >0.12

units/day IV +

therapy,then

recommends up to 30 million

but <0.5 |g/mL)

gentamicin 3 mg/

2 weeks P-lactam

units/day IV (i.e,.3-400,000

kg/day IV

alone

U/kg).In situations where the

risk of aminoglycoside use is

Ceftriaxone 2 g/day IV +

2 weeks combined

high, 4 weeks of P-lactam alone

gentamicin 3 mg/

therapy,then

may be considered; consultation

kg/day IV

2 weeks P-lactam

with infectious disease specialist

alone

should be considered.

Vancomycin 30 mg/

4 weeks

Recommended only for P-lactam

kg/day IV q12h

intolerance; aim for peak

concentration of 30-45 |g/mL

1-h post infusion and trough

concentration of 10-15 |g/mL

Vancomycin 30 mg/

2 weeks combined

Recommended by BSAC, but not

kg/day IVq12h +

therapy, then 2 weeks

by AHA

gentamicin 3 mg/

Vancomycin alone

kg/day IV

Penicillin-resistant

(MIC > 0.5 |g/mL)

See Table 9.4

"S. bovis" is the common name used to designate the group D non-enterococcal streptococci, which are common inhabitants of the intestinal flora of humans. The taxonomy of the S. bovis/S. equinus complex (herein referred to as "S. bovis complex") is evolving and currently consists of the following species: S. bovis, S. equinus, S. gal-lolyticus, S. infantarius, S. pasteurianus, and S. lutetiensis [31,57]. The significance to the clinician of knowing this nomenclature derives from the association of "S. bovis" with certain co-morbidities. Lack of awareness of the species that constitute the complex can lead to under-diagnosis of these serious underlying conditions [58]. Recent epidemiologic data from the International Collaboration on Endocarditis (ICE) has demonstrated that the proportion of IE due to S. bovis complex is increasing, accounting for 10.9% of cases before 1989, with a dramatic rise to 23.3% of cases after 1989 [59]. Therefore, an understanding of the clinical features of S. bovis complex IE is necessary.

The S. bovis complex is very similar to the viridans streptococci in terms of virulence and antimicrobial susceptibility, with the possible exception of increasing clindamycin resistance [60], a bacteriostatic antibiotic not routinely used in the treatment of IE. As such, therapeutic guidelines for these groups of pathogens are identical [2,11, 12,15,27], shown in Table 9.3.

There are, however, subtle but significant differences in the IE due to S. bovis complex. These differences can be divided into two categories: IE features and associated co-morbidities.

With respect to IE features, studies have demonstrated that patients with this disease are typically of older age, male predominance, higher rates of co-morbid illnesses, with no previously known valve disease [4,59,61-63]. Furthermore, this syndrome has a predilection for the mitral valve, although it can commonly involve multiple valves [59,62,64,65]. Recently, S. bovis complex IE has also been found to account for a higher proportion of cases among patients with prosthetic valves [59]. The data on whether S. bovis complex IE is associated with more frequent embolic and neurologic complications is conflicting [59,62-65]. The rates, however, of early surgical treatment and of mortality did not differ significantly when comparing S. bovis complex IE to viridans streptococcal IE [59,63,65,66].

The major associated comorbidity of S. bovis complex bacteremia is colonic neoplasm, mainly with S. bovis biotype I (S. gallolyticus subsp. gallolyticus as per new nomenclature) [58,59,65]. Various studies have demonstrated that 25-80% of patients with S. bovis complex bacteremia harbor a colorectal tumor [67,68]. The mechanism by which this complex of bacteria is related to neoplasia remains to be elucidated, but bacterial proteins with the potential to induce a chronic infectious or inflammatory process has been proposed [67]. Nonetheless, the association is well described enough that all patients with S. bovis complex bacteremia, including IE, need aggressive evaluation of the gastrointestinal tract, especially the colon, when clinically feasible [12,66,68,69]. Other conditions possibly associated with these pathogens include chronic liver disease [65,70] and various extra-intestinal neoplasms [68,71].

Nutritionally Variant Streptococci

The nutritionally variant streptococci (NVS) were originally identified in 1961 as a novel strain that exhibited satellitism around colonies of other bacteria [72]. These bacteria have fastidious growth characteristics, requiring complex media enriched with vitamin B6 or L-cysteine, as well as pleomorphism and variable Gram-stain reactions [73]. Recent 16S rRNA gene sequencing studies have demonstrated that the NVS are two new genera: Abiotrophia (consisting currently of only one species, A. defectiva), and Granulicatella (composed of G. adiacens, G. balaenopterae, and G. elegans) [74]. Here, they will be collectively referred to as "NVS." These bacteria are members of the normal flora of the oral cavity, as well as the gastrointestinal and genitourinary tracts [75] and account for approximately 5% of all cases of streptococcal IE [72,75]. However, because they are fastidious, it is possible that most previous cases were misdiagnosed as culture-negative IE, thus underestimating their prevalence. Routine modern blood cultures can detect the NVS, usually in 2-3 days [72,76,77], although the sensitivity of this method is unknown. Subsequent microbiologic identification and antimicrobial susceptibility testing should be performed. Although there are no specific ClSi (NCCLS) interpretive criteria for Abiotrophia or Granulicatella spp., current practice is to use the criteria for "Streptococcus spp. other than S. pneumoniae" [73,78,79].

NVS IE usually occurs as a result of bacteremia in patients with underlying valve injury [72]. Although it is generally characterized by a slow and indolent course, it is usually more severe, and associated with higher morbidity and mortality, than IE due to viridans streptococci or enterococci [72,80,81]. In a review of 30 cases of NVS IE, the bacteriological failure rate was 41%, despite the in vitro bactericidal effects of antibiotics in two-thirds of cases; approximately 27% of patients required replacement with a prosthetic valve and approximately 20% of patients developed fatal CHF or major systemic emboli [72,81]. The slow growth rate of the bacteria and the production of large amounts of exopolysaccharide in vivo may account for the difficulties encountered in treatment [80]. Another contributing factor is antimicrobial susceptibility. When using CLSI (NCCLS) laboratory criteria, almost 50% of NVS may not be susceptible to penicillin, although there are species-specific variations in sensitivities, with A. defectiva being more commonly non-susceptible [72,73,78,82]. Susceptibility testing with aminoglycosides has demonstrated variable sensitivities [83]. Lack of susceptibility has also been demonstrated with other P-lactams (e.g., cefazolin, cefotaxime) [73,78] as well as macrolides (e.g., azithromycin) [73]. Most strains have, however, remained susceptible to clindamycin, rifampin, quinolones, and van-comycin [78,82,83]. As such, IE due to NVS is treated according to the recommendations for treating enterococci (see Table 9.4) [12,52].

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