Viridans Group Streptococci in Pediatric Leukemia and Stem Cell Transplant: Review of a Risk-stratified Guideline for Empiric Vancomycin in Febrile Neutropenia.

Viridans group streptococci (VGS) are an important cause of sepsis in immunosuppressed children. We reviewed the effectiveness of risk-stratified addition of vancomycin to empiric febrile neutropenia therapy among 107 children with leukemia or undergoing an allogeneic transplant. Of 19 VGS bacteremia episodes, 78.9% were susceptible to risk-stratified antibiotics including 100% from high-risk patients. All blood cultures were flagged positive within 24 hours.

Brain Abscess in a Patient with Osteopetrosis: A Rare Complication

Brain abscess formation is extremely rare in patients with osteopetrosis. Herein, we report a case of viridans streptococci brain abscess in an immunocompromised child diagnosed with osteopetrosis. The patient presented with a sudden change in mental status and convulsions. Radiological evaluation revealed a temporal lobe brain abscess, and intravenous antibiotherapy was started immediately. The patient underwent abscess drainage, and laboratory investigation of pus material revealed viridans streptococci.

Antibiotic Resistance of Viridans Group Streptococci Isolated from Dental Plaques.

Viridans group streptococci (VGS) are a common cause of infective endocarditis, and dental plaque is the major source of these bacteria. The present study examined the antibiotic resistance of 635 VGS isolates obtained from dental plaques. Isolates from supragingival plaques were identified using the rapid ID 32 Strep and mini API reader (bioMérieux, France), and minimal inhibitory concentrations (MICs) were determined by a broth microdilution method. High rates of resistance to ampicillin and tetracycline were detected among the isolates. The most resistant species were Streptococcus sanguinis and Streptococcus salivarius. Among the 635 isolates, 9.1% were resistant to erythromycin, and 20.6% to tetracycline. All isolates were sensitive to vancomycin. Resistance to amoxicillin was observed in 0.2% of all isolates. In this study, we showed the incidence of antimicrobial resistance and the susceptibility patterns among 635 VGS isolates from dental plaque.

Metabolic changes associated with adaptive resistance to daptomycin in Streptococcus mitis-oralis.

BACKGROUND: Viridans group streptococci of the Streptococcus mitis-oralis subgroup are important endovascular pathogens. They can rapidly develop high-level and durable non-susceptibility to daptomycin both in vitro and in vivo upon exposure to daptomycin. Two consistent genetic adaptations associated with this phenotype (i.e., mutations in cdsA and pgsA) lead to the depletion of the phospholipids, phosphatidylglycerol and cardiolipin, from the bacterial membrane. Such alterations in phospholipid biosynthesis will modify carbon flow and change the bacterial metabolic status. To determine the metabolic differences between daptomycin-susceptible and non-susceptible bacteria, the physiology and metabolomes of S. mitis-oralis strains 351 (daptomycin-susceptible) and 351-D10 (daptomycin non-susceptible) were analyzed. S. mitis-oralis strain 351-D10 was made daptomycin non-susceptible through serial passage in the presence of daptomycin. RESULTS: Daptomycin non-susceptible S. mitis-oralis had significant alterations in glucose catabolism and a re-balancing of the redox status through amino acid biosynthesis relative to daptomycin susceptible S. mitis-oralis. These changes were accompanied by a reduced capacity to generate biomass, creating a fitness cost in exchange for daptomycin non-susceptibility. CONCLUSIONS: S. mitis-oralis metabolism is altered in daptomycin non-susceptible bacteria relative to the daptomycin susceptible parent strain. As demonstrated in Staphylococcus aureus, inhibiting the metabolic changes that facilitate the transition from a daptomycin susceptible state to a non-susceptible one, inhibits daptomycin non-susceptibility. By preventing these metabolic adaptations in S. mitis-oralis, it should be possible to deter the formation of daptomycin non-susceptibility.

Strain-level analysis of gut-resident pro-inflammatory viridans group Streptococci suppressed by long-term cotrimoxazole prophylaxis among HIV-positive children in Zimbabwe.

Antimicrobials have become a mainstay of healthcare in the past century due to their activity against pathogens. More recently, it has become clear that they can also affect health via their impact on the microbiota and inflammation. This may explain some of their clinical benefits despite global increases in antimicrobial resistance (AMR) and reduced antimicrobial effectiveness. We showed in a randomized controlled trial of stopping versus continuing cotrimoxazole prophylaxis among HIV-positive Zimbabwean children taking antiretroviral therapy (ART), that continuation of cotrimoxazole persistently suppressed gut-resident viridans group streptococcal species (VGS) that were associated with intestinal inflammation. In this addendum, we provide a broader overview of how antibiotics can shape the microbiota and use high read-depth whole metagenome sequencing data from our published study to investigate whether (i) the impact of cotrimoxazole on gut VGS and (ii) VGS associated inflammation, is attributable to strain-level variability. We focus on S. salivarius, the VGS species that was most prevalent in the cohort and for which there was sufficient genome coverage to differentiate strains. We demonstrate that suppression of S. salivarius by cotrimoxazole is not strain specific, nor did stool concentration of the pro-inflammatory mediator myeloperoxidase vary by S. salivarius strain. We also show that gut-resident S. salivarius strains present in this study population are distinct from common oral strains. This is the first analysis of how cotrimoxazole prophylaxis used according to international treatment guidelines for children living with HIV influences the gut microbiome at the strain-level. We also provide a detailed review of the literature on the mechanisms by which suppression of VGS may act synergistically with cotrimoxazole's anti-inflammatory effects to reduce gut inflammation. A greater understanding of the sub-clinical effects of antibiotics offers new insights into their responsible clinical use.

Endocarditis Caused by Highly Penicillin-Resistant Viridans Group Streptococci: Still Room for Vancomycin-Based Regimens.

Optimal treatment options remain unknown for infective endocarditis (IE) caused by penicillin-resistant (PEN-R) viridans group streptococcal (VGS) strains. The aims of this study were to report two cases of highly PEN-R VGS IE, perform a literature review, and evaluate various antibiotic combinations in vitro and in vivo The following combinations were tested by time-kill studies and in the rabbit experimental endocarditis (EE) model: PEN-gentamicin, ceftriaxone-gentamicin, vancomycin-gentamicin, daptomycin-gentamicin, and daptomycin-ampicillin. Case 1 was caused by Streptococcus parasanguinis (PEN MIC, 4 µg/ml) and was treated with vancomycin plus cardiac surgery. Case 2 was caused by Streptococcus mitis (PEN MIC, 8 µg/ml) and was treated with 4 weeks of vancomycin plus gentamicin, followed by 2 weeks of vancomycin alone. Both patients were alive and relapse-free after ≥6 months follow-up. For the in vitro studies, except for daptomycin-ampicillin, all combinations demonstrated both synergy and bactericidal activity against the S. parasanguinis isolate. Only PEN-gentamicin, daptomycin-gentamicin, and daptomycin-ampicillin demonstrated both synergy and bactericidal activity against the S. mitis strain. Both strains developed high-level daptomycin resistance (HLDR) during daptomycin in vitro passage. In the EE studies, PEN alone failed to clear S. mitis from vegetations, while ceftriaxone and vancomycin were significantly more effective (P < 0.001). The combination of gentamicin with PEN or vancomycin increased bacterial eradication compared to that with the respective monotherapies. In summary, two patients with highly PEN-R VGS IE were cured using vancomycin-based therapy. In vivo, regimens of gentamicin plus either ß-lactams or vancomycin were more active than their respective monotherapies. Further clinical studies are needed to confirm the role of vancomycin-based regimens for highly PEN-R VGS IE. The emergence of HLDR among these strains warrants caution in the use of daptomycin therapy for VGS IE.

Identificación y sensibilidad a los antimicrobianos de aislados de estreptococos del grupo viridans provenientes de pacientes internados en un hospital universitario de la ciudad de Buenos Aires / Identification and antibiotic susceptibility of viridans group streptococci isolates recovered from patients hospitalized at a teaching hospital in Buenos Aires City

Los estreptococos del grupo viridans (EGV) son agentes causales de infecciones localizadas e invasivas. Dada la gravedad de las infecciones producidas por EGV sumada a las escasas comunicaciones actuales en nuestro país, los objetivos de este trabajo fueron la identificación y el estudio de la sensibilidad a los antibióticos de aislados caracterizados como EGV, recuperados de pacientes internados, para actualizar el conocimiento sobre el perfil de resistencia y la epidemiología de las infecciones ocasionadas por EGV. Se recuperaron 132 aislados de EGV en el Hospital de Clínicas «José de San Martín¼ en el período 2011-2015. La identificación se realizó mediante pruebas convencionales y espectrometría de masas (Matrix Assisted Laser Desorption Ionization - Time of Flight Mass Spectrometry). El grupo Streptococcus anginosus fue el más frecuente (42%) seguido por el grupo Streptococcus mitis (33%). Dentro del grupo S. mitis se excluyó a Streptococcus pneumoniae. El 100% de los aislados fue sensible a ertapenem, linezolid y vancomicina; el 96,9% a cef-triaxona y cefepima. Se encontró un 25,8% de resistencia a penicilina (I+R) fundamentalmente en aislados de grupo S. mitis. La resistencia a tetraciclina fue del 27,2% y solo 2/132 aislados fueron resistentes a levofloxacina. Los valores de CIM de gentamicina oscilaron entre 0,5 y 32 -og/ml. El 17,4% de los aislados presentó resistencia a eritromicina sin diferencia significativa en la distribución de fenotipos M y MLS. Los resultados muestran la importancia de la vigilancia continua de las infecciones producidas por estos microorganismos con el fin de generar aportes para la elección de la terapia antibiótica adecuada.

Members of the viridans group streptococci (VGS) are the cause of local and invasive infections. Due to the severity of these infections and taking into account that reports regarding epidemiological aspects are scarce, the aims of this work were the identification and the study of the antibiotic susceptibility profiles of the isolates recovered from patients that were hospitalized in order to find out about the resistance level and the epidemiology of infections in which VGS are involved. A hundred and thirty two isolates identified as VGS were isolated at Hospital de Clínicas «José de San Martín¼ during the period 2011-2015. The identification was performed by biochemical test and mass spectrometry by Matrix Assisted Laser Desorption Ionization -Time of Flight Mass Spectrometry. Streptococcus anginosus group was prevalent (42%) followed by Streptococcus mitis group (33%). In the latter, isolates of Streptococcus pneumoniae were excluded. All the VGS isolates were susceptible to ertapenem, meropenem, linezolid and vancomycin; 25.8% were resistant (I+R) to penicillin, being prevalent in the S. mitis group. Regarding ceftriaxone and cefepime 96.9% of the isolates were susceptible. Only two isolates were resistant to levofloxacin, 27.2% to tetracycline and it was not found high level resistance to gentamycin (MIC range 0.5-32 µg/ml). Resistance to erythromycin was 17.4% with no significant difference between M and MLS phenotypes. The most active antibiotics were in addition to ceftriaxone and cefepime, vancomycin, ertapenem, meropenem and linezolid. These results highlight the importance of the continuous surveillance of the infections caused by VGS in order to predict a correct antibiotic therapy.

[Identification and antibiotic susceptibility of viridans group streptococci isolates recovered from patients hospitalized at a teaching hospital in Buenos Aires City]. / Identificación y sensibilidad a los antimicrobianos de aislados de estreptococos del grupo viridans provenientes de pacientes internados en un hospital universitario de la ciudad de Buenos Aires.

Members of the viridans group streptococci (VGS) are the cause of local and invasive infections. Due to the severity of these infections and taking into account that reports regarding epidemiological aspects are scarce, the aims of this work were the identification and the study of the antibiotic susceptibility profiles of the isolates recovered from patients that were hospitalized in order to find out about the resistance level and the epidemiology of infections in which VGS are involved. A hundred and thirty two isolates identified as VGS were isolated at Hospital de Clínicas «José de San Martín¼ during the period 2011-2015. The identification was performed by biochemical test and mass spectrometry by Matrix Assisted Laser Desorption Ionization -Time of Flight Mass Spectrometry. Streptococcus anginosus group was prevalent (42%) followed by Streptococcus mitis group (33%). In the latter, isolates of Streptococcus pneumoniae were excluded. All the VGS isolates were susceptible to ertapenem, meropenem, linezolid and vancomycin; 25.8% were resistant (I+R) to penicillin, being prevalent in the S. mitis group. Regarding ceftriaxone and cefepime 96.9% of the isolates were susceptible. Only two isolates were resistant to levofloxacin, 27.2% to tetracycline and it was not found high level resistance to gentamycin (MIC range 0.5-32µg/ml). Resistance to erythromycin was 17.4% with no significant difference between M and MLS phenotypes. The most active antibiotics were in addition to ceftriaxone and cefepime, vancomycin, ertapenem, meropenem and linezolid. These results highlight the importance of the continuous surveillance of the infections caused by VGS in order to predict a correct antibiotic therapy.

Antibiotic susceptibility, cytotoxicity, and protease activity of viridans group streptococci causing endophthalmitis.

The viridans group streptococci comprise multiple species and have gained more recognition in recent years as common etiologic agents of bacterial endophthalmitis. The purpose of this study was to identify the species of human endophthalmitis isolates of viridans streptococci and to characterize their potential virulence attributes. The species of 22 endophthalmitis strains of viridans streptococci were identified by Matrix Assisted Laser Desorption Ionization Time-of-Flight. Susceptibilities to 3 antibiotics commonly used for bacterial endophthalmitis were determined. The extracellular milieu of each strain was tested for cytotoxicity of retinal pigmented epithelial cells, hemolysis of sheep erythrocytes, and protease activity using gelatin zymography. Identified species were Streptococcus mitis/oralis, S. salivarius, S. vestibularis, S. parasanguinis, S. mutans, S. constellatus, and S. gordonii. One strain of S. pseudoporcinus was also identified. All strains were sensitive to vancomycin, 77% were resistant to amikacin, and 27% had intermediate resistance to ceftazidime. Extracellular milieu from all strains except one (S. pseudoporcinus) were largely devoid of toxicity to retinal pigmented epithelial cells and sheep erythrocytes. Twelve strains, 10 of which were S. mitis/oralis, produced protease activity. Interestingly, not all of the S. mitis/oralis strains were proteolytic. These findings highlight the diversity of virulence factor production in ocular strains of the viridans streptococci not only at the group level but also at the species level.

In vitro effects of commercial mouthwashes on several virulence traits of Candida albicans, viridans streptococci and Enterococcus faecalis colonizing the oral cavity.

Oral microbiota consists of hundreds of different species of bacteria, fungi, protozoa and archaea, important for oral health. Oral mycoses, mostly affecting mucosae, are mainly caused by the opportunistic pathogen Candida albicans. They become relevant in denture-wearers elderly people, in diabetic patients, and in immunocompromised individuals. Differently, bacteria are responsible for other pathologies, such as dental caries, gingivitis and periodontitis, which affect even immune-competent individuals. An appropriate oral hygiene can avoid (or at least ameliorate) such pathologies: the regular and correct use of toothbrush, toothpaste and mouthwash helps prevent oral infections. Interestingly, little or no information is available on the effects (if any) of mouthwashes on the composition of oral microbiota in healthy individuals. Therefore, by means of in vitro models, we assessed the effects of alcohol-free commercial mouthwashes, with different composition (4 with chlorhexidine digluconate, 1 with fluoride, 1 with essential oils, 1 with cetylpyridinium chloride and 1 with triclosan), on several virulence traits of C. albicans, and a group of viridans streptococci, commonly colonizing the oral cavity. For the study here described, a reference strain of C. albicans and of streptococci isolates from pharyngeal swabs were used. Chlorhexidine digluconate- and cetylpyridinium chloride-containing mouthwashes were the most effective in impairing C. albicans capacity to adhere to both abiotic and biotic surfaces, to elicit proinflammatory cytokine secretion by oral epithelial cells and to escape intracellular killing by phagocytes. In addition, these same mouthwashes were effective in impairing biofilm formation by a group of viridans streptococci that, notoriously, cooperate with the cariogenic S. mutans, facilitating the establishment of biofilm by the latter. Differently, these mouthwashes were ineffective against other viridans streptococci that are natural competitors of S. mutans. Finally, by an in vitro model of mixed biofilm, we showed that mouthwashes-treated S. salivarius overall failed to impair C. albicans capacity to form a biofilm. In conclusion, the results described here suggest that chlorhexidine- and cetylpyridinium-containing mouthwashes may be effective in regulating microbial homeostasis of the oral cavity, by providing a positive balance for oral health. On the other side, chlorhexidine has several side effects that must be considered when prescribing mouthwashes containing this molecule.

Microbiology and clinical characteristics of viridans group streptococci in patients with cancer

ABSTRACT This study assessed the microbiology, clinical syndromes, and outcomes of oncologic patients with viridans group streptococci isolated from blood cultures between January 1st, 2013 and December 31st, 2016 in a referral hospital in Mexico using the Bruker MALDI Biotyper. Antimicrobial sensitivity was determined using BD Phoenix 100 according to CLSI M100 standards. Clinical information was obtained from medical records and descriptive analysis was performed.Forty-three patients were included, 22 females and 21 males, aged 42 ± 17 years. Twenty (46.5%) patients had hematological cancer and 23 (53.5%) a solid malignancy. The viridans group streptococci isolated were Streptococcus mitis, 20 (46.5%); Streptococcus anginosus, 14 (32.6%); Streptococcus sanguinis, 7 (16.3%); and Streptococcus salivarius, 2 (4.7%). The main risk factors were pyrimidine antagonist chemotherapy in 22 (51.2%) and neutropenia in 19 (44.2%) cases, respectively. Central line associated bloodstream infection was diagnosed in 18 (41.9%) cases. Septic shock occurred in 20.9% of patients, with an overall mortality of 18.6%. Only four S. mitis revealed penicillin-resistance.Our results are similar to those of other series, identifying these bacteria as emerging pathogens with significant morbidity and mortality in oncologic patients. The MALDI-TOF system increased the rate of viridans group streptococci isolation in this population.

Microbiology and clinical characteristics of viridans group streptococci in patients with cancer.

This study assessed the microbiology, clinical syndromes, and outcomes of oncologic patients with viridans group streptococci isolated from blood cultures between January 1st, 2013 and December 31st, 2016 in a referral hospital in Mexico using the Bruker MALDI Biotyper. Antimicrobial sensitivity was determined using BD Phoenix 100 according to CLSI M100 standards. Clinical information was obtained from medical records and descriptive analysis was performed. Forty-three patients were included, 22 females and 21 males, aged 42 ± 17 years. Twenty (46.5%) patients had hematological cancer and 23 (53.5%) a solid malignancy. The viridans group streptococci isolated were Streptococcus mitis, 20 (46.5%); Streptococcus anginosus, 14 (32.6%); Streptococcus sanguinis, 7 (16.3%); and Streptococcus salivarius, 2 (4.7%). The main risk factors were pyrimidine antagonist chemotherapy in 22 (51.2%) and neutropenia in 19 (44.2%) cases, respectively. Central line associated bloodstream infection was diagnosed in 18 (41.9%) cases. Septic shock occurred in 20.9% of patients, with an overall mortality of 18.6%. Only four S. mitis revealed penicillin-resistance. Our results are similar to those of other series, identifying these bacteria as emerging pathogens with significant morbidity and mortality in oncologic patients. The MALDI-TOF system increased the rate of viridans group streptococci isolation in this population.

Activity of dalbavancin and comparator agents against Gram-positive cocci from clinical infections in the USA and Europe 2015-16.

Background: Many infections due to Gram-positive cocci (GPC; staphylococci, streptococci and enterococci) regularly involve prolonged systemic antibiotic use. Dalbavancin has demonstrated activity against GPC isolates and has been approved for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) in adults. Objectives: To evaluate the activity of dalbavancin against GPC isolated from a variety of infection types in the USA and Europe. Methods: A total of 14 319 Staphylococcus aureus, 1992 CoNS, 3269 ß-haemolytic streptococci (BHS), 2071 Enterococcus faecalis, 936 Enterococcus faecium, 71 Enterococcus gallinarum/casseliflavus and other Enterococcus spp., 3487 Streptococcus pneumoniae and 1063 viridans group streptococci (VGS) causing clinical infections were consecutively collected (2015-16) and tested for susceptibility by broth microdilution methods. Results: All S. aureus (36.4% MRSA) isolates were susceptible to dalbavancin, teicoplanin and vancomycin, while daptomycin and linezolid showed susceptibility rates of >99.9% (according to CLSI criteria). Dalbavancin MIC results were at least 16-fold lower than these comparators against all S. aureus. Dalbavancin was the most potent agent against CoNS [62.2%/59.6% methicillin-resistant (CLSI/EUCAST)], followed by daptomycin, linezolid and vancomycin. All vancomycin-susceptible E. faecalis isolates were inhibited by dalbavancin at ≤0.25 mg/L (FDA susceptible breakpoint). Dalbavancin was very active against BHS (MIC90 0.03 mg/L) and the most active agent against S. pneumoniae and VGS (highest MIC 0.25 mg/L). Ceftriaxone, daptomycin, levofloxacin and vancomycin were also active (93.5%-100.0% susceptible) against VGS, whereas clindamycin, erythromycin, penicillin and tetracycline had lower activity. Conclusions: Dalbavancin appears to be a viable candidate for treating serious infections caused by GPC.

Viridans group streptococci bloodstream infections in neutropenic adult patients with hematologic malignancy: Single center experience.

Viridans group streptococci bloodstream infections (VGS BSI) remain a significant cause of mortality and morbidity in patients with severe neutropenia. The goal of our study was to evaluate clinical course and microbiological susceptibility of VGS BSI at our center. Retrospective analysis of all microbiologically documented bloodstream infections caused by VGS during the 9-year time period (from January 2006 until December 2014) was carried out. Only patients with severe neutropenia (< 500/µL) were included in the study. Clinical outcome and microbiological susceptibility pattern of isolates were recorded. Fifty-one individual patients with episode of VGS BSI were identified. The most frequent agent was Streptococcus mitis (23/51 cases, 45.1%). 88.2% (45/51) of patients were on recommended ciprofloxacin prophylaxis. 20/51 (39.2%) of patients suffered from mucositis at the time of diagnosis (10 patients had oral mucositis, 2 patients had bowel mucositis, and 8 patients both). Twenty-six patients (51.0%) had clinically relevant lung damage caused by VGS BSI (i.e., acute lung injury or acute respiratory distress syndrome). Twenty-four (47.0%) patients presented with bilateral lung infiltrated upon chest imaging, and two (4.0%) patients had unilateral lung infiltrates. Three patients (5.9%) died due to VGS BSI until day 28 of observation. No difference in signs of shock syndrome was observed in the patients during transplantation procedures compared to patients without transplantation as well as in a group received previous high-dose chemotherapy with cytosinarabinoside or in patients with mucositis. Only 3/51 of isolates (5.9%) were resistant to penicillin. All isolates were susceptible to empirical treatment. While the penicillin resistance of VGS remains low in middle Europe, initial antibiotic therapy of febrile neutropenia are still effective in most cases. The mortality and complication rates of VGS BSI were comparable to other studies, and no specific risk factor of shock presence could be identified.

Dalbavancin in-vitro activity obtained against Gram-positive clinical isolates causing bone and joint infections in US and European hospitals (2011-2016).

BACKGROUND: Osteomyelitis is a difficult-to-treat infection that regularly involves prolonged use of systemic antibiotics. Dalbavancin has demonstrated activity against Gram-positive isolates, and has been considered as a candidate for the treatment of osteomyelitis in adults and children. This study evaluated the activity of dalbavancin against pathogens isolated from bone and joint infections (BJI). METHODS: Eight hundred and one Staphylococcus aureus, 160 coagulase-negative staphylococci (CoNS), 164 ß-haemolytic streptococci (BHS), 82 Enterococcus faecalis and 45 viridans group streptococci (VGS) causing BJI were collected consecutively (2011-2016) and tested for susceptibility by broth microdilution methods. RESULTS: S. aureus (64.0%) was the most common pathogen associated with BJI, followed by BHS (13.1%) and CoNS (12.8%). All S. aureus (33.3% meticillin-resistant) isolates were susceptible to dalbavancin, linezolid and vancomycin, while daptomycin and clindamycin showed susceptibility rates of 99.5% and 89.0%, respectively. The minimum inhibitory concentration (MIC) results for dalbavancin were at least eight-fold lower than these comparators against all S. aureus. Dalbavancin was the most potent agent against CoNS (63.1% meticillin-resistant), followed by daptomycin, linezolid and vancomycin. All E. faecalis isolates were inhibited by dalbavancin at ≤0.25 mg/L (US Food and Drug Administration susceptibility breakpoint), except for three vancomycin-resistant isolates. High susceptibility rates for ampicillin (98.8%), daptomycin (100.0%), linezolid (100.0%) and vancomycin (95.1%) were obtained against E. faecalis. Dalbavancin was very active against BHS (MIC90 ≤0.03 µg/mL), and was the most active agent against VGS (highest MIC ≤0.06 mg/L). Ceftriaxone, daptomycin and vancomycin were also active (93.3-100.0% susceptible) against VGS, whereas clindamycin (84.4% susceptible) had marginal activity. CONCLUSION: Dalbavancin appears to be a viable candidate for treating BJI/osteomyelitis caused by Gram-positive cocci.

Activity of dalbavancin tested against Gram-positive clinical isolates causing skin and skin-structure infections in paediatric patients from US hospitals (2014-2015).

OBJECTIVES: This study provides an in vitro analysis of dalbavancin activity against isolates causing skin and skin-structure infections (SSSIs) in children. METHODS: A total of 770 Staphylococcus aureus, 167 ß-haemolytic streptococci (BHS), 42 coagulase-negative staphylococci (CoNS), 25 Enterococcus faecalis and 13 viridans group streptococci (VGS) were collected from children (<18years old) in the USA (2014-2015). RESULTS: Dalbavancin had MIC50/90 values of 0.03/0.06µg/mL against S. aureus and CoNS, including methicillin-resistant (MRSA) and -susceptible (MSSA) isolates. Dalbavancin MICs were 8-32-fold lower than those of daptomycin (MIC50/90, 0.25/0.5µg/mL), vancomycin (MIC50/90, 0.5/1µg/mL) and linezolid (MIC50/90, 1/1µg/mL) against MRSA. These agents showed 100.0% susceptibility against MRSA, and clindamycin also had a high (92.7%) susceptibility rate. Dalbavancin (MIC50/90, 0.03/0.06µg/mL) and daptomycin (MIC50/90, 0.25/0.5µg/mL) were the most active agents against CoNS. When tested against E. faecalis, dalbavancin was up to 32-fold more active than ampicillin (MIC50/90, ≤0.5/1µg/mL), daptomycin (MIC50/90, 1/1µg/mL), linezolid (MIC50/90, 1/2µg/mL) and vancomycin (MIC50/90, 1/2µg/mL). Dalbavancin (MIC50/90, 0.008/0.03µg/mL), ceftriaxone (MIC50/90, ≤0.06/≤0.06µg/mL) and penicillin (MIC50/90, ≤0.06/≤0.06µg/mL) were the most active against BHS. VGS isolates were susceptible to dalbavancin (MIC100, 0.03µg/mL), with MICs 32-64-fold lower than daptomycin (MIC50/90, 0.5/0.5µg/mL), linezolid (MIC50/90, 0.5/1µg/mL) and vancomycin (MIC50/90, 0.5/0.5µg/mL). CONCLUSIONS: Approved agents available for the treatment of SSSI in children are limited. Dalbavancin demonstrated potent in vitro activity against isolates causing SSSI in children. Developing dalbavancin for SSSI treatment in children is warranted, provided safety and tolerability are satisfactory.

Prevalence of macrolide-lincosamide resistance and multidrug resistance phenotypes in streptococcal isolates causing infections in European hospitals: Evaluation of the in vitro activity of oritavancin and comparator agents.

The aim of this study was to evaluate the prevalence of resistance to erythromycin alone (M) and to erythromycin and clindamycin (cMLSB) as well as multidrug resistance (MDR) phenotypes (resistance to at least three classes of drugs) among clinical enterococci from European countries and adjacent geographic regions. The in vitro activity of oritavancin against these isolates was also evaluated. A total of 2569 streptococci collected from 12 European countries as well as Russia, Turkey and Israel were included. A total of 9.8%, 8.1% and 6.4% of ß-haemolytic streptococci (BHS) displayed M, cMLSB and MDR phenotypes, respectively. Oritavancin (99.4-100.0% susceptible) demonstrated modal minimum inhibitory concentration (MIC) (0.03mg/L) and MIC50 (0.03mg/L) values that were the same for all BHS or subsets, including MDR. The oritavancin MIC50 value of 0.06mg/L against Streptococcus dysgalactiae was similar to those of daptomycin and penicillin (MIC50≤0.06mg/L for both). Among viridans group streptococci (VGS), 28.3%, 12.7% and 11.6% showed M, cMLSB and MDR phenotypes, respectively. Oritavancin (99.9-100.0% susceptible; MIC50/90, ≤0.008/0.06mg/L) exhibited potent in vitro activity against VGS and resistant subsets, as did vancomycin (MIC50/90, 0.5/0.5-1mg/L), daptomycin (MIC50/90, 0.25-0.5/0.5-1mg/L) and linezolid (MIC50/90, 0.5-1/1mg/L). In conclusion, rates of resistance phenotypes were higher in VGS than BHS. Oritavancin demonstrated in vitro potencies that were similar to or greater than those of comparators against this recent collection of streptococci, including drug-resistant subsets, from European and adjacent countries.

Antibiotic prophylaxis with teicoplanin on alternate days reduces rate of viridans sepsis and febrile neutropenia in pediatric patients with acute myeloid leukemia.

Intensive chemotherapy directed against acute myeloid leukemia of childhood is followed by profound neutropenia and high risk for bacterial and fungal infections, including viridans group streptococci as a common cause for gram-positive septicemia. Few retrospective studies have shown the efficacy of various antibiotic prophylactic regimens in children. We retrospectively studied 50 pediatric patients treated on the AML-BFM 2004 protocol between 2005 and 2015 at St. Anna Children's Hospital and assessed the effect of antibiotic prophylaxis on the frequency of febrile neutropenia and bacterial sepsis. Fifty pediatric patients underwent 199 evaluable chemotherapy cycles. Viridans sepsis occurred after none of 98 cycles with prophylactic administration of teicoplanin/vancomycin in comparison to 12 cases of viridans sepsis among 79 cycles without systemic antibacterial prophylaxis (0 vs. 15 %, p < 0.0001). In addition, there were significantly fewer episodes of febrile neutropenia in the teicoplanin/vancomycin group (44 % vs. no prophylaxis 82 %, p < 0.0001). Severity of infection seemed to be worse when no antibiotic prophylaxis had been administered with a higher rate of intensive care unit treatment (0/98, 0 %, vs. 4/79, 5 %, p = 0.038). So far, no increase of vancomycin-resistant enterococcus isolates in surveillance cultures was noticed. Antibiotic prophylaxis with teicoplanin (or vancomycin) appears safe and feasible and resulted in eradication of viridans sepsis and decreased incidence of febrile neutropenia in pediatric AML patients. The possibility to administer teicoplanin on alternate days on an outpatient basis or at home could contribute to patient's quality of life and decrease health care costs.

Pronounced heterogeneity observed in high-level daptomycin-resistant viridans group streptococci.

Viridans group streptococci (VGS) have demonstrated high-level daptomycin resistance (HLDR) upon daptomycin exposure. This study evaluated the extent of heterogeneity and whether dose escalation or combination therapy could prevent resistance development. Five VGS strains (daptomycin MICs 0.25-2mg/L) were evaluated. In vitro models utilised simulated daptomycin dosages of 4, 6, 8 and 12mg/kg with estimated fCmax of 4.1, 6.6, 8.6 and 12.9mg/L, respectively. Time-kill studies included fCmax simulations of daptomycin alone or combined with ceftriaxone, gentamicin, linezolid, rifampicin or vancomycin. Population analyses were performed on daptomycin-containing and non-containing agar plates. Extreme heterogeneity was observed in four strains with daptomycin population MICs 4-512-fold higher than broth microdilution. Whilst Streptococcus gordonii 1649 did not consistently develop HLDR, its population MIC was above the established daptomycin breakpoint. In vitro modelling demonstrated initial kill by daptomycin in all strains within 8h, with substantial re-growth by 24h despite increasing daptomycin. Daptomycin kill curves also displayed resistance development by 24h. However, synergy or additivity was noted for most regimens and strains. Synergy was most notable with daptomycin plus linezolid or rifampicin. Overall, daptomycin plus ceftriaxone or gentamicin were the most potent regimens. Gentamicin or rifampicin with daptomycin were least additive. For combination regimens with colonies isolated at 24h, HLDR was reduced 16-64-fold (MICs 4-16mg/L). Daptomycin monotherapy for VGS led to rapid development of HLDR likely due to extreme heterogeneity. Combination therapy suppressed or minimised the degree of resistance although the mechanism remains unknown.