Endocarditis Caused by Penicillin‐Resistant Viridans Streptococci: 2 Cases and Controversies in Therapy

e The development of high-level daptomycin resistance (HLDR; MIC of >256 mg/liter) after exposure to daptomycin has recently been reported in viridans group streptococcus (VGS) isolates. Our study objectives were as follows: to know whether in vitro development of HLDR after exposure to daptomycin was common among clinical isolates of VGS and Streptococcus bovis; to determine whether HLDR also developed during the administration of daptomycin to treat experimental endocarditis caused by the daptomycin-susceptible, penicillin-resistant Streptococcus mitis strain S. mitis 351; and to establish whether combination with gentamicin prevented the development of HLDR in vitro and in vivo. In vitro studies were performed with 114 VGS strains (mitis group, 92; anginosus group, 10; mutans group, 8; and salivarius group, 4) and 54 Streptococcus bovis strains isolated from 168 consecutive patients with infective endocarditis diagnosed between 1995 and 2010. HLDR was only observed after 24 h of exposure to daptomycin in 27% of the mitis group, including 27% of S. mitis isolates, 47% of S. oralis isolates, and 13% of S. sanguis isolates. In our experimental model, HLDR was detected in 7/11 (63%) and 8/12 (67%) isolates recovered from vegetations after 48 h of daptomycin administered at 6 mg/kg of body weight/24 h and 10 mg/kg/24 h, respectively. In vitro, time-kill experiments showed that daptomycin plus gentamicin was bactericidal against S. mitis 351 at tested concentrations of 0.5 and 1 times the MIC and prevented the development of HLDR. In vivo, the addition of gentamicin at 1 mg/kg/8 h to both daptomycin arms prevented HLDR in 21 out of 23 (91%) rabbits. Daptomycin plus gentamicin was at least as effective as vancomycin plus gentamicin. In conclusion, HLDR develops rapidly and frequently in vitro and in vivo among mitis group streptococci. Combining daptomycin with gentamicin enhanced its activity and prevented the development of HLDR in most cases.

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confidence: 99%

Early In Vitro and In Vivo Development of High-Level Daptomycin Resistance Is Common in Mitis Group Streptococci after Exposure to Daptomycin

García-de-la-Mària

Pericàs

Rı́o

et al. 2013

“…Several studies also indicated that full expression of resistance necessitates mutations both in the pbp genes and in other genes, of which only a few have been determined, namely, in the ciaRH, cpoA, and murMN loci (8,9,14). The same mechanism has also been found in viridians streptococci, which are occasionally responsible for human infections (18,26). Very recent reports also demonstrated the implication of PBP mutations in S. agalactiae presenting a decreased susceptibility to penicillin (4, 17, 21).…”

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confidence: 99%

Penicillin-Binding Protein Gene Alterations in Streptococcus uberis Isolates Presenting Decreased Susceptibility to Penicillin

Haenni¹,

Galofaro²,

Ythier

et al. 2010

Streptococcus uberis is an environmental pathogen commonly causing bovine mastitis, an infection that is generally treated with penicillin G. No field case of true penicillin-resistant S. uberis (MIC > 16 mg/liter) has been described yet, but isolates presenting decreased susceptibility (MIC of 0.25 to 0.5 mg/liter) to this drug are regularly reported to our laboratory. In this study, we demonstrated that S. uberis can readily develop penicillin resistance in laboratory-evolved mutants. The molecular mechanism of resistance (acquisition of mutations in penicillin-binding protein 1A [PBP1A], PBP2B, and PBP2X) was generally similar to that of all other penicillin-resistant streptococci described so far. In addition, it was also specific to S. uberis in that independent resistant mutants carried a unique set of seven consensus mutations, of which only one (Q 554 E in PBP2X) was commonly found in other streptococci. In parallel, independent isolates from bovine mastitis with different geographical origins (France, Holland, and Switzerland) and presenting a decreased susceptibility to penicillin were characterized. No mosaic PBPs were detected, but they all presented mutations identical to the one found in the laboratory-evolved mutants. This indicates that penicillin resistance development in S. uberis might follow a stringent pathway that would explain, in addition to the ecological niche of this pathogen, why naturally occurring resistances are still rare. In addition, this study shows that there is a reservoir of mutated PBPs in animals, which might be exchanged with other streptococci, such as Streptococcus agalactiae, that could potentially be transmitted to humans.Penicillin resistance has been particularly well studied for the human pathogen Streptococcus pneumoniae (5, 15). In this organism, resistance occurs through modifications of penicillin-binding proteins (PBPs), leading to a decreased affinity for the drug. These modifications include mutations and/or mosaics in PBP2X and PBP2B, as well as in PBP1A for the highly resistant isolates (20). Several studies also indicated that full expression of resistance necessitates mutations both in the pbp genes and in other genes, of which only a few have been determined, namely, in the ciaRH, cpoA, and murMN loci (8,9,14). The same mechanism has also been found in viridians streptococci, which are occasionally responsible for human infections (18,26). Very recent reports also demonstrated the implication of PBP mutations in S. agalactiae presenting a decreased susceptibility to penicillin (4, 17, 21). In contrast, the highly pathogenic Streptococcus pyogenes, which has been widely exposed to penicillin for decades, is apparently incapable of acquiring clinical resistance in vivo (22), even though laboratory mutants presenting decreased susceptibilities were reported (11). Thus, the capacity to develop penicillin resistance varies among different bacteria belonging to the same genus.S. pneumoniae is primarily a human pathogen, while S. agalactiae infects humans and ...

“…occasionally responsible for infections (21,24,34). In these microbes, modifications of the penicillin-binding proteins (PBPs) leading to a decreased affinity for the drug are at the forefront of the resistance mechanism.…”

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confidence: 99%

Mutations in Penicillin-Binding Protein (PBP) Genes and in Non-PBP Genes during Selection of Penicillin-Resistant Streptococcus gordonii

Haenni

Moreillon

2006

Penicillin resistance in Streptococcus spp. involves multiple mutations in both penicillin-binding proteins (PBPs) and non-PBP genes. Here, we studied the development of penicillin resistance in the oral commensal Streptococcus gordonii. Cyclic exposure of bacteria to twofold-increasing penicillin concentrations selected for a progressive 250-to 500-fold MIC increase (from 0.008 to between 2 and 4 g/ml). The major MIC increase (>35-fold) was related to non-PBP mutations, whereas PBP mutations accounted only for a 4-to 8-fold additional increase. PBP mutations occurred in class B PBPs 2X and 2B, which carry a transpeptidase domain, but not in class A PBP 1A, 1B, or 2A, which carry an additional transglycosylase domain. Therefore, we tested whether inactivation of class A PBPs affected resistance development in spite of the absence of mutations. Deletion of PBP 1A or 2A profoundly slowed down resistance development but only moderately affected resistance in already highly resistant mutants (MIC ‫؍‬ 2 to 4 g/ml). Thus, class A PBPs might facilitate early development of resistance by stabilizing penicillin-altered peptidoglycan via transglycosylation, whereas they might be less indispensable in highly resistant mutants which have reestablished a penicillin-insensitive cell wall-building machinery. The contribution of PBP and non-PBP mutations alone could be individualized in DNA transformation. Both PBP and non-PBP mutations conferred some level of intrinsic resistance, but combining the mutations synergized them to ensure high-level resistance (>2 g/ml). The results underline the complexity of penicillin resistance development and suggest that inhibition of transglycosylase might be an as yet underestimated way to interfere with early resistance development.Penicillin resistance was well studied in pathogenic Streptococcus pneumoniae as well as in some other Streptococcus spp. occasionally responsible for infections (21,24,34). In these microbes, modifications of the penicillin-binding proteins (PBPs) leading to a decreased affinity for the drug are at the forefront of the resistance mechanism. Those modifications include mutations and/or mosaics in PBP 2X, PBP 2B, and sometimes PBP 1A (25). DNA transformation experiments also indicated that full expression of resistance necessitates the cotransfer of both PBP mutations and mutations located outside the PBP genes, of which only a few have been determined, namely, in the ciaRH, cpoA, and murMN loci (10,14,17). In contrast, penicillin-resistant clinical isolates were never observed in phylogenetically related and highly pathogenic Streptococcus pyogenes isolates (28), in spite of long-lasting exposure to the drug. Penicillin-resistant S. pyogenes isolates are apparently also difficult to obtain in the laboratory. Thus, the success of developing penicillin resistance differs among various organisms belonging to the same genus.In the experiments described below, we studied the spontaneous development of penicillin resistance in cultures of Streptococcus gordonii expose...