Combination Of Daptomycin Research Articles

Addition of daptomycin to levofloxacin increased the efficacy of levofloxacin monotherapy against a methicillin-susceptible Staphylococcus aureus strain in experimental meningitis and prevented development of resistance in vitro.

Introduction. Daptomycin and levofloxacin were tested as monotherapies and in combination against the antibiotic-susceptible S. aureus strain MSSA 1112 in a rabbit meningitis model and the effect of the combination on induction of resistance was determined in vitro. Hypothesis/Gap Statement. Treatment combination might be more efficacious than the monotherapies regarding antibacterial efficacy in vivo and development of resistance. Aim. To demonstrate a synergy of the antibiotic combination daptomycin and levofloxacin in experimental meningitis, and also its ability to reduce the emergence of resistance against the antibiotics in vitro. Methodology. Changes of the susceptibility to fluoroquinolones and daptomycin were determined by the measurement of the MIC and mutations were detected by whole genome sequence comparison of the mutants with the parent strain MSSA 1112. Meningitis was induced by intracisternal inoculation of 105 c.f.u. (colony forming unit) of MSSA 1112 and treatment was started 10 h later by injection of daptomycin (15 mg kg−1) and levofloxacin (10 mg kg−1) standard doses. Cerebrospinal fluid (CSF) samples were repeatedly collected during therapy in order to determine killing rates and results of bactericidal activity were expressed in Δlog10c.f.u. ml-1 over 8 h. Results. The combination of daptomycin with levofloxacin was significantly (P<0.001) superior to levofloxacin monotherapy and increased the antibacterial activity of daptomycin. In vitro, MSSA 1112 was cycled over 6 days with either increasing concentrations of levofloxacin or daptomycin or with a combination of levofloxacin with half of the MIC of daptomycin or daptomycin with half of the MIC of levofloxacin leading to mutations in target genes as identified by whole genome sequence analysis. Addition of low concentration of daptomycin (0.25 mg l−1) reduced levofloxacin-induced resistance in vitro. Addition of levofloxacin in low concentration (0.125 mg l−1) did not influence daptomycin-induced resistance. Conclusion. These findings highlight the lack of reciprocal interference of antibiotics in combination with regard to the development of resistance.

Successful Treatment of Vancomycin-Resistant Enterococcus Bacteremia With a Combination of Daptomycin and Tigecycline in an Infant who Underwent Heart-Lung Transplantation

Successful Treatment of Vancomycin-Resistant Enterococcus Bacteremia With a Combination of Daptomycin and Tigecycline in an Infant who Underwent Heart-Lung Transplantation

In-vitro Activity of Tigecycline versus Daptomycin against Clinical Isolates of Enterococcus Species

Introduction: Tigecycline is a potential therapeutic agent for multidrug resistant gram positive and gram negative organisms. The clinical efficacy of synergic combination of daptomycin with betalactam antibiotics have been described against various species of Enterococcus isolates. Aim: To detect the in-vitro activity of tigecycline and daptomycin against Enterococcus species and their antimicrobial activity with Vitek 2 automated system. Materials and Methods: This was a cross-sectional study conducted at Department of Microbiology, Vinayaka Mission’s Kirupananda Variyar (VMKV) Medical College and Hospitals, Salem, Tamil Nadu, India. Isolates of Enterococcus obtained over a period of two years from March 2016 - March 2018 from various clinical samples were identified by standard biochemical method and their antimicrobial susceptibility pattern was determined. Minimum Inhibitory Concentration (MIC) of tigecycline and daptomycin was determined by Vitek 2 automated system. Analysis of data was done by using frequency distribution and percentage. Results: Out of 211 Enterococcus isolates studied, 23 (10.90%) isolates showed decreased susceptibility to daptomycin with MIC of ≥8 µg/mL. All isolates showed 100% susceptibility to tigecycline. Conclusion: The present study showed potent antimicrobial activity of tigecycline against various species of Enterococcus. Decreased susceptibility to daptomycin has been observed among the study isolates. Further clinical investigations are required to know the potential benefits of these agents in therapy.

1250. Development of Linezolid and Daptomycin Resistance in Vancomycin Resistant Enterococcus faecium (VRE) during prolonged treatment for Intraabdominal Abscess

BackgroundVancomycin-resistant enterococci (VRE) are nosocomial pathogens with extensive intrinsic and acquired antimicrobial resistance (AMR) mechanisms. We report a case in which intraabdominal (IA) and blood cultures grew linezolid and daptomycin resistant VRE (DLVRE).MethodsWe report a case of DLVRE bacteremia after prolonged treatment with linezolid and daptomycin.ResultsThe patient was a 65-year-old female with a history of multiple abdominal surgeries who presented for elective incisional hernia repair. Her post-operative course was complicated by the development of loculated IA abscesses. A drain was placed into the largest abscess, and aspiration cultures were polymicrobial containing vancomycin-resistant E. faecium (Isolate 1). The patient was treated meropenem, fluconazole and linezolid for 6 weeks. Clinical and radiographic improvement was achieved. However, 4 days after competing antibiotics she developed recurrent abdominal pain and a leukocytosis. Daptomycin was chosen out of concern for long-term linezolid toxicity and IA cultures demonstrated new linezolid resistance (Isolate 2, LVRE). After an additional three weeks of therapy, she developed a catheter-associated bloodstream infection (CLABSI). Blood cultures revealed daptomycin-resistant LVRE bacteremia (Isolate 3, DLVRE). She was started empirically on a combination of ceftaroline and daptomycin, her PICC line removed, and her blood cultures cleared. Her antibiotic course is presented in Figure 1 and resistance patterns of the VRE in Table 1. ConclusionIn this patient, an IA abscess known to harbor VRE developed resistance to both linezolid and daptomycin during prolonged treatment with both agents. Ultimately, the patient experienced an episode of CLABSI DLVRE. Limited data exists on appropriate antibiotic choice in such challenging situations. Based on prior clinical and experimental data, we elected to use daptomycin in conjunction with ceftaroline for synergy, and the patient achieved the desired clinical response, clearance of her blood cultures and diminishing size of her IA abscess. Further work is needed to elucidate the best course of treatment for patients with VRE requiring long-term antibiotic therapy and for those who have developed extensively drug-resistant E. faecium.Disclosures All Authors: No reported disclosures

Pre-clinical Impact of the Synergistic Mechanism of Daptomycin and Ceftaroline on Patients with Methicillin-resistant Staphylococcus aureus Bacteremia Infections.

Our study aims at assessing the pre-clinical impact of the synergistic mechanism of Daptomycin (DAP) and Ceftaroline (CFT) on patients with Methicillin-Resistant Staphylococcus aureus Bacteremia infections (MRSAB). A systematic overview was conducted by searching PubMed, Oxford academic, and Cochrane library up to June 2020. All English- language clinical trials, in vitro studies, and case reports related to the synergistic drug therapy for MRSAB. In the case of MRSAB infections, we examined two different in vitro studies that showed effective synergism with DAP and CFT. The Minimum Inhibitory Concentration (MIC) range observed for each is as follow: DAP 0.125-1 mg/L, CFT 0.38-1 mg/L, DAP + CFT 0.094-0.5 mg/L, vancomycin (VAN) 0.75-2 mg/L, VAN + CFT 0.25-2 mg/L. DAP + CFT combination displayed the most efficacy with the lowest MIC. The statistical analysis performed showed that DAP + CFT obtained significantly lower fractional inhibitory concentration (FIC) values (0.941 ± 0.328) compared with VAN + CFT. In vitro activities of regimens tested on DAP non-susceptibility and VAN intermediate after 96 hours showed DAP 8.29 ± 0.03a log10 CFU/mL, VAN 6.82 ± 0.04a log10 Colony Forming Unit (CFU)/mL, CFT 4.63 ± 0.19a log10 CFU/mL, DAP + CFT 1.15 ± 0.20b log10 CFU/mL, VAN + CFT 3.18 ± 0.49a log10 CFU/mL. (a meaning significantly different than DAP plus CFT, P< equal to 0.001b meaning therapeutic enhancement combination was defined as ≥ 2 log10 CFU/ml reduction over the most active single agent). Based on these results, although DAP was not susceptible, the Colony Forming Unit (CFU) for DAP and CFT had the best therapeutic results. In vitro studies have shown that a combination DAP and CFT is more efficacious than the combination of VAN and CFT in MRSA bacteremia infections. The synergic effects of DAP (bactericidal) and CFT (bactericidal) is statistically significant, in recent trials, warranting promising evidence for its use in complicated bacteremia infection.

AORTIC ROOT ABSCESS: A RARE COMPLICATION OF STAPHYLOCOCCUS EPIDERMIDIS PROSTHETIC VALVE ENDOCARDITIS

TOPIC: Chest Infections TYPE: Fellow Case Reports INTRODUCTION: Aortic root abscess is a lethal complication of infective endocarditis. Here, we report a case of aortic root abscess that occurred as a complication of S. epidermidis prosthetic valve endocarditis, which is a rare cause of aortic abscess. CASE PRESENTATION: 71-year-old woman with complex cardiac history including a bioprosthetic aortic valve replacement, ascending aorta aneurysm repair, and coronary artery bypass graft x4 presented to the ER with worsening chest pain, fevers, chills and rigors. On arrival, temperature was 97.5°F heart rate was 61 beats/min, respiratory rate was 20 per minute and blood pressure was 139/82 mm Hg. On exam, she had a grade 4/6 ejection systolic murmur, heard best at the right upper sternal border radiating to carotids. Laboratory investigations showed hemoglobin, 10.5 g/ dL; total leukocyte count, 10 k/uL with 80% neutrophils; platelet count, 311 k/uL; and sedimentation rate, 74 mm/hr. Rest of the labs were normal. She tested negative for SARS-Cov-2 by polymerase chain reaction (PCR). Blood cultures grew isolated Staphylococcus epidermidis. She was persistently bacteremic on vancomycin monotherapy and required ceftaroline and daptomycin combination therapy for clearance of bacteremia. Transesophageal echo cardiography was obtained which showed an area of echolucency adjacent to the posterior aortic valve annulus suggestive of abscess. PET CT was obtained, confirmed the diagnosis of aortic abscess. She was referred to Mayo Clinic. She underwent, extensive debridement of previously implanted tissue aortic valve and entire root complex, coronary artery bypass grafting and aortic root replacement. DISCUSSION: Aortic root abscess is a life-threatening complication of aortic valve endocarditis, known to occur in patients with native and prosthetic aortic valves. Staphylococcus aureus is the reported as most common cause. Persistent fever, shortness of breath, chest pain and other signs of severe aortic regurgitations are the most common presentation. Aggressive surgical debridement and medical therapy are the key to treatment. If untreated, can result in severe valvular dysfunction, fistula formation, perforation of cusps, pseudoaneurysm, obstruction of coronary flow or fatal arrhythmia. Even with surgery, reported mortality remains high 12.2-30%. CONCLUSIONS: Aortic root abscess should be considered as a diagnosis in persistently febrile and bacteremic patients with prosthetic valve endocarditis and should be treated promptly with surgical debridement and reconstruction. REFERENCE #1: Chen G-J, Lo W-C, Tseng H-W, Pan S-C, Chen Y-S, Chang S-C. Outcome of surgical intervention for aortic root abscess: a meta-analysis. Eur J Cardiothorac Surg 2018;53:807–14 DISCLOSURES: No relevant relationships by Rosa Cruz Torres, source=Web Response No relevant relationships by Dorothy Kenny, source=Web Response No relevant relationships by Sanu Rajendraprasad, source=Web Response No relevant relationships by Manasa Velagapudi, source=Web Response

In Vitro Anti-Biofilm Activity of Bacteriophage K (ATCC 19685-B1) and Daptomycin against Staphylococci.

The purpose of the present study was to investigate anti-staphylococcal activity of daptomycin and bacteriophage K, alone or in combination, against biofilm-producers and non-producers S. aureus and S. epidermidis strains, under biofilm forming and cells’ proliferation conditions. Daptomycin and bacteriophage K (ATCC 19685B1), in different concentrations, were tested against 10 Staphylococcus aureus and 10 S. epidermidis, characterized by phenotypes and genotypes. The quantitative microtiter plate (crystal violet, CV), methylthiazoltetrazolium (MTT), and growth curve (GC) assays were performed. No statistically significant difference was found between species, whereas daptomycin alone performed better using medium and high concentrations of the drug and bacteriophage K was more active against strains with higher susceptibility, by CV and MTT assays. Best results were achieved using both agents combined in high concentrations. Bacteriophage K was effective within 3.8 and 2.4 h, depending on the concentration used, by the GC assay. Combination of daptomycin with bacteriophage K was more effective against staphylococci, depending on the concentrations used and strains’ susceptibility. Further studies are needed to evaluate if this approach might be a choice for prevention or therapy of biofilm-associated infections.

Combination of ceftaroline and daptomycin as treatment for complicated osteomyelitis

Osteomyelitis is an infection involving bone. Staphylococcus aureus is the pathogen most frequently implicated; less frequently involved are other gram-positive organisms, such as Staphylococcus epidermidis, and also gram-negative organisms. The...

Biofilm Time-Kill Curves to Assess the Bactericidal Activity of Daptomycin Combinations against Biofilm-Producing Vancomycin-Resistant Enterococcusfaecium and faecalis.

Introduction: E. faecium and E. faecalis are responsible for 13.9% of hospital-acquired infections with frequent resistance to vancomycin (82.6% of E. faecium, 9.5% of E. faecalis). Medical device infections secondary to enterococci often require combination therapy due to impaired activity against biofilm embedded cells. In vitro data demonstrate synergistic activity of daptomycin combinations. Using a novel, biofilm time-kill approach, we evaluated whether daptomycin combinations maintained synergy against biofilm-producing E. faecium and E. faecalis. Methods: Broth microdilution (BMD) and biofilm MIC (bMIC) values for daptomycin, ampicillin, ceftriaxone, fosfomycin, and rifampin were determined against biofilm-producing E. faecium and E. faecalis. Daptomycin combination bMIC values were determined in the presence of biologic concentrations of other antimicrobials. Synergy was evaluated against two E. faecalis (R6981, R7808) and two E. faecium (5938 and 8019) using a previously described biofilm time-kill method. Synergy was defined as ≥2 log10 CFU/cm2 reduction over the most active agent alone. Bactericidal activity was defined as ≥3 log10 CFU/cm2 reduction. Results: Daptomycin bMICs were 2–8-fold higher than BMD. In the presence of other antimicrobials, daptomycin bMICs were reduced ≥ two-fold in dilutions. Ceftriaxone and ampicillin demonstrated the most potent combinations with daptomycin, yielding synergy against three of four strains. Daptomycin plus rifampin was synergistic against E. faecium 5938 and E. faecalis 6981 and produced bactericidal kill. The combination of daptomycin plus fosfomycin displayed synergy solely against E. faecalis 6981. Conclusions: Daptomycin combinations with beta-lactams demonstrated promising synergistic activity against both E. faecium and E. faecalis. While daptomycin plus rifampin yielded bactericidal results, the effect was not seen across all organisms. These combinations warrant further evaluation to determine the optimal dose and response.

Combination Therapy of Chloramphenicol and Daptomycin for the Treatment of Infective Endocarditis Secondary to Multidrug Resistant Enterococcus faecium.

A 38-years-old female with an aortic valve replacement presented to an outside hospital (OSH) with fevers and malaise. Blood cultures revealed VRE which was resistant to linezolid, resistant to ampicillin, non-susceptible to daptomycin (MIC of 8 mcg/mL), and exhibited susceptibility to gentamicin. The patient was therefore initiated on intravenous (IV) daptomycin 6 mg/kg q24h and gentamicin IV 1 mg/kg q8h. However, after 14 days of therapy with daptomycin and gentamicin, the patient was transferred to our institution for the management of cardiogenic shock and hypoxemic respiratory failure. Given the concern for treatment failure, her antimicrobial regimen was changed to IV chloramphenicol 12.5 mg/kg every 6 hours with IV daptomycin 10 mg/kg every 48 hours given an estimated creatinine clearance of 30 mL/minutes. In vitro susceptibilities for chloramphenicol were performed which confirmed susceptibility. A transesophageal echocardiogram revealed a possible abscess at the left coronary cusp and aortic valve dehiscence. The patient underwent aortic valve replacement with aortic root reconstruction. The aortic valve culture grew VRE susceptible to linezolid but resistant to ampicillin and doxycycline. The patient was deemed clinically cured after 42 days of combination therapy with daptomycin and chloramphenicol. After 6 years of follow-up, the patient has not had a recurrent VRE infection. To our knowledge, this is the first case of endocarditis secondary to VRE that was successfully managed with the combination of daptomycin and chloramphenicol.

Daptomycin in combination with rosuvastatin induced blood creatine phosphokinase elevation

We present the case of a 73-year-old male patient who was hospitalised with infective endocarditis, and report an elevation in his blood creatine phosphokinase (CPK) after receiving daptomycin and rosuvastatin...

Efficacy of Antistaphylococcal Lysin LSVT-1701 in Combination with Daptomycin in Experimental Left-Sided Infective Endocarditis Due to Methicillin-Resistant Staphylococcus aureus.

We utilized the rabbit model of aortic valve infective endocarditis to examine the combined efficacy of the lysin LSVT-1701 plus daptomycin. The combination of LSVT-1701 plus daptomycin was highly effective at reducing methicillin-resistant Staphylococcus aureus (MRSA) counts in target tissue. When given for four daily doses, both lysin dose regimens in combination with daptomycin sterilized all target tissues. These findings suggest that LSVT-1701 warrants further clinical evaluation as an adjunctive therapy for the treatment of invasive MRSA infections.

Dosing Considerations for Combination Antistaphylococcal β-Lactam and Glyco/lipopeptide Salvage Therapy for Resistant Gram-Positive Infections: A Systematic Review.

The objective of this systematic review is to evaluate dosing regimens of combination salvage regimens used as part of infectious disease pharmacotherapy. A systematic review was conducted on PubMed, MEDLINE, Scopus, ProQuest Central, and CINAHL through March 2021 using the following terminology: "combination" OR "Seesaw" OR "see-saw" OR "salvage" AND "infection" OR "resistant infection" OR "Gram-positive" AND "beta-lactam" OR "cephalosporin" OR "carbapenem" OR "monobactam" OR "glycopeptide" OR "lipopeptide." Following the application of inclusion and exclusion criteria, 8 pieces of literature were ultimately included in this review. Vancomycin in combination with another agent was most commonly prescribed as initial or empirical therapy. The most common combination salvage therapy regimen consisted of daptomycin in doses up to 12 mg/kg IV every 24 hours with ceftaroline 200 to 600 mg IV every 8 to 12 hours. Although the duration of combination salvage therapy varied drastically, blood culture clearance was typically observed within 24 hours. Antimicrobial-resistant Gram-positive organisms have posed an emergent threat to antimicrobial stewardship initiatives. Utilizing either a glycopeptide or lipopeptide antibiotic in combination with an antistaphylococcal β-lactam antibiotic has demonstrated efficacy in treating resistant bacteria. This work describes the heterogeneity of dosing regimens and seeks to define an optimal dose, duration, and combination of antibiotics. Combination salvage therapy has demonstrated efficacy and safety in treatment of resistant Gram-positive infections. It appears the combination of daptomycin and ceftaroline can clear resistant infections expeditiously.

Low prevalence of tissue detection of cefepime and daptomycin used as empirical treatment during revision for periprosthetic joint infections: results of a prospective multicenter study.

Data demonstrating that antibiotics administered intraoperatively in patients with surgical revision for periprosthetic joint infection achieve concentrations exceeding minimal inhibitory concentrations of the identified bacteria at the surgical site when the new implant is inserted are lacking. We prospectively included patients with periprosthetic joint infection operated with one- or two-stage replacement during which cefepime (2g)-daptomycin (10mg/kg) combination was administered intravenously as intraoperative empirical antibiotic treatment. Three biopsies (two bones and one synovial membrane) were taken from each patient just before the insertion of the new implant. Eighteen adults of median age 68 years were included. Knee was involved in 10 patients (55.6%) and surgery consisted in one-/two-stage replacement in 11/7 patients. A tourniquet was used during the intervention in the 10 patients with knee prosthesis. Among 54 tissue samples, cefepime and daptomycin were detected respectively in 35 (64.8%) and 21 (38.9%) cases (P=0.01). A total of 17 bacteria dominated by staphylococci (n=14) were identified in 10 patients; tissue inhibitory quotient calculated in 51 samples was >1 in 22 cases (43.1%) for cefepime and in 16 cases (31.4%) for daptomycin. The proportion of tissue samples with detectable antibiotic was significantly higher in hip versus knee prosthesis (P=0.03). The present study suggests that intraoperative empirical administration of cefepime-daptomycin combination during septic prosthetic joint replacement results in a high proportion of tissue samples in which at least one of the two antibiotics was not detected or at a low concentration despite satisfactory concomitant blood serum concentrations.

Broad-Spectrum Antibiotics for Breast Expander/Implant Infection: Treatment-Related Adverse Events and Outcomes.

Despite best practices, infection remains the most common complication after breast reconstruction with expanders and implants, ranging from 2% to 29%. Empiric broad-spectrum antibiotics are frequently used in nonsurgical treatment of implant-associated infections in an effort to salvage the reconstruction. Pitfalls of antibiotherapy include adverse events, vascular access site complications, and drug resistance. Our goals were to describe management of implant infections with broad-spectrum antibiotics, review treatment related adverse events, and report on outcomes of therapy. A retrospective review was carried out to identify patients who were treated with intravenous (IV) antibiotics for periprosthetic infection. Patient characteristics, surgical details, and antibiotic therapy-related adverse events were collected. Eventual outcome related to expander/implant salvage was noted. A total of 101 patients (111 treatment episodes) were identified. Mean duration of antibiotic treatment was 18 days (range, 1-40 days). The most commonly used parenteral treatment was a combination of daptomycin with piperacillin-tazobactam (65%) or an alternative agent (16%). Fifty-nine percent of treatment episodes resulted in salvage of the expander or implant. Thirty-five percent treatment episodes were associated with 1 or more adverse events: diarrhea (12.6%), rash (10%), vaginal candidiasis (3.6%), agranulocytosis/neutropenic fever (3.6%), nausea (3.6%), urinary complaint (0.9%), myositis (0.9%), headache (0.9%), vascular line occlusion (1.8%), deep vein thrombosis (1.8%), and finger numbness (0.9%). No patients developed Clostridium difficile colitis. Five episodes (4%) needed discontinuation of antibiotics because of severe adverse events. The prosthesis was explanted in 3 of the cases of discontinued treatment. Our findings show favorable outcomes and well-tolerated adverse effects with broad-spectrum parenteral antibiotherapy for periprosthetic infection. However, every effort should be made to deescalate therapy by narrowing the spectrum or limiting the duration, to minimize adverse events and development of bacterial resistance. Treating surgeons need to carefully weigh benefits of therapy and be aware of potential complications that might necessitate discontinuation of treatment.

1611. Evaluating Clinical Outcomes and Efficacy of Daptomycin in Combination with a Beta-Lactam for the Treatment of Vancomycin-Resistant Enterococcus (VRE) Bacteremia

BackgroundIn-vitro studies have shown synergistic bactericidal activity with daptomycin (DAP) plus β-lactam antimicrobials against vancomycin resistant enterococci (VRE). There is a paucity of data regarding clinical outcomes with this combination in VRE bloodstream infections (BSI). The purpose of this study was to assess the efficacy of DAP plus a β-lactam with in-vitro activity vs. other therapies for treatment of VRE BSI.MethodsIRB-approved, single-center, retrospective study of patients with VRE BSI from 01/2018-09/2019. Patients were excluded if < 18 years old, pregnant, or incarcerated. The primary outcome was time-to-microbiological clearance. Secondary outcomes included infection-related mortality, 30-day all-cause mortality, and incidence of recurrent BSI within 30 days of index culture. Targeted DAP doses were ≥ 8mg/kg and based on MIC. Factors associated with significance for outcomes, via univariate analysis, were evaluated with multivariable logistic regression (MLR), removed in a backward-step approach.ResultsA total of 85 patients were included, 23 of which received DAP plus a β-lactam. The comparator arm included linezolid or DAP monotherapy. Patients with combination therapy had significantly higher Charlson Comorbidity Index (CCI) (p=0.013) and numerically higher Pitt Bacteremia scores (PBS) (p=0.087) (Table 1). There was no difference seen in the primary outcome (Table 2). Secondary outcomes are provided in Table 2. The presence of polymicrobial infection and higher PBS were significantly associated with infection-related mortality (p=0.008 and p=0.005, respectively) by MLR. A Mann Whitney U test indicated that presence of infection-related mortality was greater for patients with higher MICS (U=20.5, p=0.06). The presence of an underlying source may be related to recurrence of BSI (p=0.075).Table 1: Patient Characteristics Table 2. Primary and Secondary Outcomes ConclusionWe did not find a significant difference in time-to-microbiological clearance, although patients treated with DAP and a β-lactam had higher CCI and PBS. These results are limited by retrospective design, small sample size, and potential selection bias. Prospective randomized studies are needed to further validate these findings.Disclosures All Authors: No reported disclosures

697. 8 Years of Characteristics and Outcomes of Patients with MRSA Endocarditis Based on Vancomycin Minimum Inhibitory Concentration: Experience at a Tertiary Care Hospital

BackgroundVancomycin has been the mainstay of treatment for methicillin-resistant Staphylococcus aureus (MRSA) infective endocarditis (IE). MRSA reduced susceptibility to vancomycin is a growing threat. Data assessing the effect of vancomycin reduced susceptibility on outcomes is limited. Our study aimed to evaluate characteristics and outcomes of MRSA-related IE based on the minimum inhibitory concentration (MIC) to vancomycinCharacteristics and outcomes of 51 patients with MRSA-related endocarditis according to the minimal inhibitory concentration (MIC) to vancomycin MethodsIRB approval was obtained for a retrospective cohort study at a tertiary care center. Records of hospitalized adults diagnose with IE by ICD-9/ICD-10 CM codes were identified from 2011 to 2018. 51 patients had MRSA-related IE and were selected for the analysis. Demographic, microbiologic, Imaging and outcome variables were obtained. Characteristics and outcomes of patients with MRSA-related IE according to the MIC to vancomycin (≤ vs. > 1 mcg/mL) were comparedResults35.3% of patients had a MIC > 1 mcg/mL. 59% were men, mean age was 46±3 years old. 65% acquired the infection through injection drug use. Only 3.9% of patients had prosthetic valve IE. 35.3% had tricuspid valve vegetation, 25.5% mitral valve and 21.6% aortic valve vegetation. Two patients had IE possibly related to a PICC-line infection; both of these patients had a MIC to vancomycin >1 mcg/mL, suggestive of prolonged antibiotic therapy. All patients with MRSA-related IE were started empirically on vancomycin. Patients with a MIC > 1 mcg/mL were more likely to be switched to a combination of daptomycin and ceftaroline, compared to those with a MIC ≤ 1 mcg/mL (44.4% vs. 6.1%; P=0.001). 25.4% underwent valvular replacement within 6 months. 12% died within 90 days. MRSA-related IE with MIC > 1mcg/mL did not confer and an increase risk in in-hospital mortality (11.1% vs. 15.2%; P=0.67) or mortality at 90 days (11.1% vs. 12.5%; P=0.89).ConclusionIn this single-center experience, we found that in 8 years 35% of patients with MRSA-related IE had MIC >1 mcg/mL. This is an alarming finding. Although our study did not reach statistic significance we didn’t found difference in valvular surgery requirement or mortality among those with MIC > 1mcg/d as compared to those with a more sensitive MRSA strain. A study with more power or a metha-analysis will be require to better answer this question.Disclosures All Authors: No reported disclosures

Dalbavancin, Vancomycin and Daptomycin Alone and in Combination with Cefazolin against Resistant Phenotypes of Staphylococcus aureus in a Pharmacokinetic/Pharmacodynamic Model.

The most efficacious antimicrobial therapy to aid in the successful elimination of resistant S. aureus infections is unknown. In this study, we evaluated varying phenotypes of S. aureus against dalbavancin (DAL), vancomycin (VAN), and daptomycin (DAP) alone and in combination with cefazolin (CFZ). The objective of this study was to observe whether there was a therapeutic improvement in adding a beta-lactam to a glycopeptide, lipopeptide, or a lipoglycopeptide. We completed a series of in vitro tests including minimum inhibitory concentration testing (MIC) of the antimicrobials in combination, time-kill analysis (TKA), and a 168 h (7-day) one-compartment pharmacokinetic/pharmacodynamic (PK/PD) model on two daptomycin non-susceptible (DNS), vancomycin intermediate S. aureus strains (VISA), D712 and 6913. Results from our MIC testing demonstrated a minimum 2-fold and a maximum 32-fold reduction in MIC values for DAL, VAN, and DAP in combination with CFZ, in contrast to either agent used alone. The TKAs completed on four strains paralleled the enhanced activity demonstrated via the combination MICs. In the one-compartment PK/PD models, the combination of DAP plus CFZ or VAN plus CFZ resulted in a significant (p < 0.001) improvement in bactericidal activity and overall reduction in CFU/ml over the 7-day period. While the addition of CFZ to DAL improved time to bactericidal activity, DAL alone demonstrated equal and more sustained overall activity compared to all other treatments. The use of DAL alone, with or without CFZ and the combinations of VAN or DAP with CFZ appear to result in increased bactericidal activity against various recalcitrant S. aureus phenotypes.

Updates on Combination Therapy for Methicillin-Resistant Staphylococcus aureus Bacteremia

Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is associated with a large clinical burden and high rates of treatment failure with first-line treatment options. Literature for combination antimicrobial therapies for initial treatment or salvage therapy in the setting of persistent bacteremia is developing. Various combination strategies have emerged for the treatment of MRSA bacteremia, including vancomycin or daptomycin in combination with either anti-staphylococcal penicillins, early- and late-generation cephalosporins, ceftaroline, trimethoprim-sulfamethoxazole, or fosfomycin. When used as second-line or salvage therapy, evidence suggests use of these combinations shorten the duration of bacteremia. More recently, data have emerged evaluating this strategy for initial therapy, although results are conflicting. Use of combination therapy for MRSA bacteremia may shorten bacteremia duration, but the optimal combination, doses, timing of use, and exact impact on clinical outcomes are still evolving.

Cloxacillin or fosfomycin plus daptomycin combinations are more active than cloxacillin monotherapy or combined with gentamicin against MSSA in a rabbit model of experimental endocarditis.

In vitro and in vivo activity of daptomycin alone or plus either cloxacillin or fosfomycin compared with cloxacillin alone and cloxacillin plus gentamicin were evaluated in a rabbit model of MSSA experimental endocarditis (EE). Five MSSA strains were used in the in vitro time-kill studies at standard (105-106 cfu/mL) and high (108 cfu/mL) inocula. In the in vivo EE model, the following antibiotic combinations were evaluated: cloxacillin (2 g/4 h) alone or combined with gentamicin (1 mg/kg/8 h) or daptomycin (6 mg/kg once daily); and daptomycin (6 mg/kg/day) alone or combined with fosfomycin (2 g/6 h). At standard and high inocula, daptomycin plus fosfomycin or cloxacillin were bactericidal against 4/5 and 5/5 strains, respectively, while cloxacillin plus gentamicin was bactericidal against 3/5 strains at standard inocula but against none at high inocula. Fosfomycin, cloxacillin, gentamicin and daptomycin MIC/MBCs of the MSSA-678 strain used in the EE model were: 8/64, 0.25/0.5, 0.25/0.5 and 1/8 mg/L, respectively. Adding gentamicin to cloxacillin significantly reduced bacterial density in vegetations compared with cloxacillin monotherapy (P = 0.026). Adding fosfomycin or cloxacillin to daptomycin [10/11 (93%) and 8/11 (73%), respectively] significantly improved the efficacy of daptomycin in sterilizing vegetations [0/11 (0%), P < 0.001 for both combinations] and showed better activity than cloxacillin alone [0/10 (0%), P < 0.001 for both combinations] and cloxacillin plus gentamicin [3/10 (30%), P = 0.086 for cloxacillin plus daptomycin and P = 0.008 for fosfomycin plus daptomycin]. No recovered isolates showed increased daptomycin MIC. The addition of cloxacillin or fosfomycin to daptomycin is synergistic and rapidly bactericidal, showing better activity than cloxacillin plus gentamicin for treating MSSA EE, supporting their clinical use.