**7. Penicillin**

as positive blood cultures after 7 days of appropriate antibiotic therapy, relapse following a course of therapy with appropriate antibiotics, or a positive valve culture). It is notable that bacteriologic failure was seen despite the sensitivity of the organisms to the antibiotics used in two thirds of the cases. About 31% of the patients required surgery. Mortality rate was 17% which was higher than that of endocarditis caused by enterococci or viridans streptococci [41]. Similarly a more recent review of 29 cases of solely *Granulicatella* endocarditis by Adam et al. showed very high rates of complications and adverse outcomes. Incidence of heart failure was 30%, embolism was seen in 30% of patients and perivalvular abscess was seen in 11%. The mortality rate was 17%. The average vegetation size was 16 mm (31). They found that aortic (44%) and the mitral (38%) valves were the most commonly effected and multivalvular

Large vegetation sizes are associated with increased risk of systemic embolism in infective endocarditis. Case studies reveal large vegetation sizes with infective endocarditis caused by NVS (greater than 10 mm in 7 out of 8 cases reviewed by Lin et al., and average vegetation size of 16 mm in a case series of 29 patients by Adam et al.) [50]. These findings correlate with the

Endocarditis caused by NVS is associated with high rates of infectious intracranial cerebral aneurysms although the exact incidence is unknown. Having a low threshold for obtaining imaging of the CNS is reasonable even for patients with vague complaints such as severe localized headaches or mild confusion [3]. Many infectious intracranial cerebral aneurysms resolve by antibiotic treatment with reductions in size in the first 1–2 weeks. The risk of rup-

Endocarditis caused by NVS is associated with 13% of aortic valve damage and 11% of mitral valve damage. If not recognized on a timely basis, these patients may present with congestive heart failure as the first presenting manifestation of the infection [51]. Congestive heart failure is a potential complication of valvular destruction which can necessitate heart valve

Aorto-RV fistula is a rare complication of *A. defectiva* endocarditis that requires early surgical intervention for closure [52]. Development of hemophagocytic lymphohistiocytosis was

Endocarditis caused by NVS has rarely been reported in children. According to a review of 13 pediatric cases in children, 69% had underlying heart disease [54]. Similar to adult patients, endocarditis caused by NVS in pediatric populations also appears to be associated with high complication rates including severe valvular damage, surgical valve replacement and sys-

Antimicrobial susceptibility testing is very difficult for *Abiotrophia* and *Granulicatella* due to their fastidious nature. In addition, the results of susceptibility testing may not be accurate or

reported in a previously healthy patient with *A. defectiva* endocarditis [53].

high rates of systemic embolism seen in endocarditis caused by NVS.

ture decreases with time on antibiotic therapy [3].

involvement was (13%) [50].

46 Advanced Concepts in Endocarditis

replacement surgery.

temic embolization [54, 55].

**6. Treatment**

NVS have the highest in vitro penicillin resistance compared to any other streptococci. The rate of penicillin resistance among NVS appears to be rising over the years. While an earlier study by Cooksey and Swenson in 1979 [59] and Gephart and Washington in 1982 [60] showed no isolates had a penicillin MIC >1 μg/ml, subsequent studies showed significantly increasing penicillin resistance; Bosley and Facklam in 1990 [61] noted 9% rate of resistance to penicillin and Alberti in 2016 [62] reported 14% rate of penicillin resistance among NVS. It is also notable that the method of penicillin susceptibility testing has changed over the years. Douglas et al. (1994) [63] found that while historical method of penicillin susceptibility testing by reference dilution method did not find penicillin resistance, when same NVS isolates were tested with E test, 7% penicillin resistance was detected. The high rate of penicillin resistance among VNS appears also to be consistent among NVS isolates from pediatric infections [64].

Instead, broth microdilution MIC testing by laboratories experienced in such testing is recommended. CLSI suggests broth microdilution MIC testing in Cation adjusted Mueller-Hinton

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E test is proven to be a rapid and simple method for MIC estimation for NVS, comparable to

CLSI consensus guidelines also emphasize that cases of *Abiotrophia* or *Granulicatella* infections can be managed by following the treatment recommendations in the medical literature without antimicrobial susceptibility testing. The antimicrobial susceptibility testing can be reserved for those cases where there is persistent infection, clinical failure, allergy or intolerance to the drugs of choice and possible resistance to the drugs that might be prescribed. Infectious disease specialists or other expert clinicians should make all susceptibility testing

Penicillin resistance is often associated with resistance or decreased susceptibility to other

However, overall cephalosporin susceptibility among NVS appears to be higher compared to penicillin. In addition, A*. defectiva* appears to have higher susceptibility to 3rd generation cephalosporins compared to *G. adiacens*. According to a large review of susceptibilities of antibiotic susceptibility testing for 132 clinical NVS isolates from blood cultures that were isolated from 2008 to 2014 at Los Angeles hospitals by Albierti et al., Ceftriaxone susceptibility was 61.4% and Cefotaxime susceptibility was 43.2% among all isolates. *A. defectiva* was more susceptible than *G. adiacens* to the third generation cephalosporins (94.6% vs. 18.9% for Cefotaxime and 100% vs. 43.3% for ceftriaxone). Ceftriaxone susceptibility breakpoint was MIC ≤1 μg/ml as per CLSI M45 [62, 69]. Touhy et al. had found a similar susceptibility pattern of susceptibility for ceftriaxone; they had observed that 83% of the *A. defectiva* isolates and 63% of *G. adiacens* isolates were susceptible to Ceftriaxone by using MIC ≤0.5 susceptibility breakpoint [66]. Zheng et al. reported that out of 15 isolates of *Abiotrophia* and *Granulicatella*, 9 were resistant to Ceftriaxone (MIC of >2 μg/ml), 13 were resistant to Cefuroxime (MIC of >2 μg/ml) [64]. All six isolates of *G. adiacens* in their review were resistant to Ceftriaxone [64]. Albierti et al. noted that some of the isolates that were resistant to ceftriaxone still remained susceptible to Ceftaroline. (51.6% of *G. adiacens* isolates resistant to ceftriaxone with an MIC ≥4 μg/ml had Ceftaroline MICs of ≤1 μg/ml). On the other hand, 32% of *G. adiacens* isolates that were resistant to ceftriaxone (MIC ≥4) had Ceftaroline MICs ≥4 μg/ml. These isolates were noted to be resistant to penicillin (MIC ≥4 μg/ml). The Ceftaroline MIC90 for all isolates were

broth with 2.5–5% lysed horse blood and 0.001% pyridoxal HCl [69].

lower compared to Cefotaxime or Ceftriaxone (2 versus >4 μg/ml) [62].

*G. adiacens* isolates appear to be fairly consistent across various studies.

Resistance to higher generations of cephalosporins have been reported such as Cefepime

Species related differences of penicillin or cephalosporin sensitivities in determining antibiotic choices remains to be investigated. The high rates of ceftriaxone resistance among

(2 out of 21 isolates) [70] and Cefotaxime (7 out of 28 isolates were resistant) [65].

broth microdilution MIC testing [63].

decision and test interpretation [69].

beta-lactam antibiotics including ceftriaxone [66].

**7.3. Cephalosporins**

According to antibiotic susceptibility testing of 132 isolates by Albierti et al. in 2016, only 33% of the 132 isolates were susceptible to penicillin and 14% were resistant with an MIC ≥4 μg/ml. The remaining 53% of the isolates had penicillin MICs in the intermediate category (0.25–2 μg/ml) [62]. Liao et al. reported 50% of their isolates (14 out of 28 isolates) had intermediate susceptibility to penicillin [65].

There appears to be differences in penicillin susceptibilities among different species of NVS. Albierti et al. showed that penicillin susceptibility is much less among *A. defectiva* compared to *G. adiacens* (10.8% vs. 38.9%). *G. elegans* isolates are highly susceptible to penicillin with MIC of 0.03 μg/ml (n = 5) [62].

In an earlier study by Touhy et al. in a review of 39 isolates from 1995 to 1999, similar to Albierti et al.'s findings, *G. adiacens* penicillin sensitivity was higher than that of *A. defectiva*; 55 vs. 8% respectively. [66].

#### **7.1. Penicillin tolerance**

It is notable that clinical failures of treatment have frequently been described even for penicillin susceptible strains when appropriate antibiotics are given. Holloway et al. described a phenomenon of penicillin tolerance among NVS which minimum bactericidal concentration (MBC) significantly exceeded (greater than 32) the minimum inhibitory concentration (MIC) that would lead to a slower antibiotic effect and potentially a worse clinical response. In addition to the usual nutritional supplements of vitamin B6 and cysteine to the plates, by adding penicillinase to the subculture medium and a staphylococcal streak across the plates they showed that even though all tested isolates were susceptible to penicillin (MICs of the strains ranged from 0.05 to 0.4 U of penicillin per ml), 100% of the isolates were penicillin tolerant. The isolates did not show any penicillin tolerance if the subculture was supplemented only with pyridoxal and cysteine [67]. Therefore, in order to identify penicillin tolerance and not misidentify the strains as penicillin sensitive, it is necessary to add penicillinase to the medium in addition to the usual growth supplements, pyridoxal HCl, cysteine and staphylococcal streak.

The slow growth rate of NVS is also thought to be responsible from poor response to antibiotic treatment. NVS generation time is 2–3 h while viridans streptococci generation time is 40–50 min [2, 41, 68].

#### **7.2. Susceptibility testing**

According to the latest consensus guidelines from the Clinical and Laboratory Standards Institute (CLSI) for antimicrobial susceptibility testing for infrequently isolated or fastidious bacteria, disk diffusion test for *Abiotrophia* and *Granulicatella* species is not recommended. Instead, broth microdilution MIC testing by laboratories experienced in such testing is recommended. CLSI suggests broth microdilution MIC testing in Cation adjusted Mueller-Hinton broth with 2.5–5% lysed horse blood and 0.001% pyridoxal HCl [69].

E test is proven to be a rapid and simple method for MIC estimation for NVS, comparable to broth microdilution MIC testing [63].

CLSI consensus guidelines also emphasize that cases of *Abiotrophia* or *Granulicatella* infections can be managed by following the treatment recommendations in the medical literature without antimicrobial susceptibility testing. The antimicrobial susceptibility testing can be reserved for those cases where there is persistent infection, clinical failure, allergy or intolerance to the drugs of choice and possible resistance to the drugs that might be prescribed. Infectious disease specialists or other expert clinicians should make all susceptibility testing decision and test interpretation [69].

#### **7.3. Cephalosporins**

to penicillin and Alberti in 2016 [62] reported 14% rate of penicillin resistance among NVS. It is also notable that the method of penicillin susceptibility testing has changed over the years. Douglas et al. (1994) [63] found that while historical method of penicillin susceptibility testing by reference dilution method did not find penicillin resistance, when same NVS isolates were tested with E test, 7% penicillin resistance was detected. The high rate of penicillin resistance among VNS appears also to be consistent among NVS isolates from pediatric infections [64]. According to antibiotic susceptibility testing of 132 isolates by Albierti et al. in 2016, only 33% of the 132 isolates were susceptible to penicillin and 14% were resistant with an MIC ≥4 μg/ml. The remaining 53% of the isolates had penicillin MICs in the intermediate category (0.25–2 μg/ml) [62]. Liao et al. reported 50% of their isolates (14 out of 28 isolates) had inter-

There appears to be differences in penicillin susceptibilities among different species of NVS. Albierti et al. showed that penicillin susceptibility is much less among *A. defectiva* compared to *G. adiacens* (10.8% vs. 38.9%). *G. elegans* isolates are highly susceptible to penicillin

In an earlier study by Touhy et al. in a review of 39 isolates from 1995 to 1999, similar to Albierti et al.'s findings, *G. adiacens* penicillin sensitivity was higher than that of *A. defectiva*;

It is notable that clinical failures of treatment have frequently been described even for penicillin susceptible strains when appropriate antibiotics are given. Holloway et al. described a phenomenon of penicillin tolerance among NVS which minimum bactericidal concentration (MBC) significantly exceeded (greater than 32) the minimum inhibitory concentration (MIC) that would lead to a slower antibiotic effect and potentially a worse clinical response. In addition to the usual nutritional supplements of vitamin B6 and cysteine to the plates, by adding penicillinase to the subculture medium and a staphylococcal streak across the plates they showed that even though all tested isolates were susceptible to penicillin (MICs of the strains ranged from 0.05 to 0.4 U of penicillin per ml), 100% of the isolates were penicillin tolerant. The isolates did not show any penicillin tolerance if the subculture was supplemented only with pyridoxal and cysteine [67]. Therefore, in order to identify penicillin tolerance and not misidentify the strains as penicillin sensitive, it is necessary to add penicillinase to the medium in addition to the usual growth supplements, pyridoxal HCl, cysteine and staphylococcal streak. The slow growth rate of NVS is also thought to be responsible from poor response to antibiotic treatment. NVS generation time is 2–3 h while viridans streptococci generation time is

According to the latest consensus guidelines from the Clinical and Laboratory Standards Institute (CLSI) for antimicrobial susceptibility testing for infrequently isolated or fastidious bacteria, disk diffusion test for *Abiotrophia* and *Granulicatella* species is not recommended.

mediate susceptibility to penicillin [65].

with MIC of 0.03 μg/ml (n = 5) [62].

55 vs. 8% respectively. [66].

**7.1. Penicillin tolerance**

48 Advanced Concepts in Endocarditis

40–50 min [2, 41, 68].

**7.2. Susceptibility testing**

Penicillin resistance is often associated with resistance or decreased susceptibility to other beta-lactam antibiotics including ceftriaxone [66].

However, overall cephalosporin susceptibility among NVS appears to be higher compared to penicillin. In addition, A*. defectiva* appears to have higher susceptibility to 3rd generation cephalosporins compared to *G. adiacens*. According to a large review of susceptibilities of antibiotic susceptibility testing for 132 clinical NVS isolates from blood cultures that were isolated from 2008 to 2014 at Los Angeles hospitals by Albierti et al., Ceftriaxone susceptibility was 61.4% and Cefotaxime susceptibility was 43.2% among all isolates. *A. defectiva* was more susceptible than *G. adiacens* to the third generation cephalosporins (94.6% vs. 18.9% for Cefotaxime and 100% vs. 43.3% for ceftriaxone). Ceftriaxone susceptibility breakpoint was MIC ≤1 μg/ml as per CLSI M45 [62, 69]. Touhy et al. had found a similar susceptibility pattern of susceptibility for ceftriaxone; they had observed that 83% of the *A. defectiva* isolates and 63% of *G. adiacens* isolates were susceptible to Ceftriaxone by using MIC ≤0.5 susceptibility breakpoint [66]. Zheng et al. reported that out of 15 isolates of *Abiotrophia* and *Granulicatella*, 9 were resistant to Ceftriaxone (MIC of >2 μg/ml), 13 were resistant to Cefuroxime (MIC of >2 μg/ml) [64]. All six isolates of *G. adiacens* in their review were resistant to Ceftriaxone [64].

Albierti et al. noted that some of the isolates that were resistant to ceftriaxone still remained susceptible to Ceftaroline. (51.6% of *G. adiacens* isolates resistant to ceftriaxone with an MIC ≥4 μg/ml had Ceftaroline MICs of ≤1 μg/ml). On the other hand, 32% of *G. adiacens* isolates that were resistant to ceftriaxone (MIC ≥4) had Ceftaroline MICs ≥4 μg/ml. These isolates were noted to be resistant to penicillin (MIC ≥4 μg/ml). The Ceftaroline MIC90 for all isolates were lower compared to Cefotaxime or Ceftriaxone (2 versus >4 μg/ml) [62].

Resistance to higher generations of cephalosporins have been reported such as Cefepime (2 out of 21 isolates) [70] and Cefotaxime (7 out of 28 isolates were resistant) [65].

Species related differences of penicillin or cephalosporin sensitivities in determining antibiotic choices remains to be investigated. The high rates of ceftriaxone resistance among *G. adiacens* isolates appear to be fairly consistent across various studies.

European Society of Cardiology (ESC) Clinical Practice Guidelines include Ceftriaxone in their recommendations for treatment of endocarditis caused by *A. defectiva* or *Granulicatella* slightly differing from AHA recommendations. ESC recommendation for treatment of IE caused by *A. defectiva or Granulicatella* is Penicillin G, Ceftriaxone or Vancomycin for 6 weeks, combined with an aminoglycoside at least for the first 2 weeks [71].

(MIC ≤0.06 μg/ml for both antibiotics) [62]. Touhy et al. [66] found that 3 isolates of *A. adiacens* (out of 27 total isolates) and 7 isolates of *G. defectiva* (out of 12 total isolates) had increased MICs of Meropenem (0.5 μg/ml). These isolates also had penicillin MICs ≥0.5 μg/ml. One of their isolates of *A*. *adiacens* had a high MIC for Meropenem (MIC of 1 μg/ml) which was isolated from a patient with suspected intervertebral disc space infection who had received a prolonged course of various antibiotics including beta-lactams. This particular isolate was

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Resistance to quinolones among NVS is rare. 8 *G. adiacens* [62] and one *G. elegans* [70] isolates have been reported to be resistant to Levafloxacin. The case of *G. elegans* resistant to Levafloxacin was isolated from a patient with neutropenic fever with bacteremia who had previously received Levafloxacin therapy. Mechanism of NVS resistance to quinolones is yet

There are no CLSI defined sensitivity breakpoints for Daptomycin and Linezolid for NVS. Albierti et al. found that Daptomycin MICs appear to be relatively high for NVS. Daptomycin MIC90 was >4 μg/ml for *A. defectiva*, 4 μg/ml for *G adiacens* and 0.5 μg/ml for *G. elegans*. According to the CLSI breakpoint of susceptibility for viridans group Streptococci is MIC ≤1 μg/ml, majority of the tested isolates (89.4%) would be considered resistant to Daptomycin [62, 69]. The reason for relatively high Daptomycin MICs for *A. defectiva* and *G. adiacens* is not clear. This may be due to an inherent resistance of these bacteria to Daptomycin potentially due to differences in cell wall composition [62]. In a prior study a smaller number of NVS isolates (n = 10) were found to have MICs ≤0.125–2 [73]. The reason for the discrepancy in the findings of these two studies is not known and

When the breakpoint of Linezolid susceptibility for viridans group streptococci (MIC ≤2 μg/ml) is applied to NVS, all NVS would be considered susceptible to Linezolid according to one study of 132 isolates [62, 69]. It was noted that *G*. *adiacens* MIC90 for Linezolid is higher (2 μg/ml)

Rifampin appears to be one of the most effective antibiotics against NVS although the data is limited. It was shown that Rifampin had a minimal bactericidal concentration of 2 μg/ml while that of penicillin was 1 μg/ml [60]. Combination of Vancomycin and Rifampin showed synergy

also resistant to penicillin and ceftriaxone (MICs ≥8 μg/ml).

**12. Quinolones**

to be determined [62].

**13. Daptomycin and linezolid**

merits further investigation.

**14. Rifampin**

than that of *A. defectiva* and *G. elegans* (1 μg/ml) [62].
