Standard Of Care Antibiotics Research Articles

1257. A phase II Prospective Randomized Study to Assess Ceftolozane-Tazobactam in the Management of Febrile Neutropenia in Patients with Hematological Malignancies

BackgroundDespite the implementation of successful antibiotic stewardship programs, antibiotic resistance continue to emerge particularly against gram-negative bacteria. With the increase use of antibiotics in high risk patients with hematological malignancies, the empiric therapy with standard antibiotic could be inappropriate. New antibiotics may be useful to cover potential resistant pathogens. We evaluated the role of a new cephalosporin /β-lactamase inhibitor ceftolozane-tazobactam (C/T) in comparison to standard of care (SOC) antibiotics in the empiric treatment of febrile neutropenic cancer patients with hematological malignancies.MethodsWe conducted a prospective randomized open label comparative study to evaluate the safety and efficacy of C/T vs SOC antibiotics consisting of cefepime, piperacillin-tazobactam or meropenem when used in combination with gram positive antibacterial agents. Between May 2018 and March 2020, we enrolled 88 febrile neutropenic patients with hematological malignancies who presented to our emergency center. Patients received at least 72 hours of intravenous study drugs and were followed through end of IV therapy and for up to 42 days.ResultsA total of 88 patients were analyzed of whom 42 received C/T and 46 SOC antimicrobial agents. The rate of documented bloodstream infections was similar in both groups (CE-TZ 21% vs SOC 26%, p=0.61). Favorable clinical response at end of IV therapy was significantly better in the C/T arm compared to SOC therapy (88% vs 72%, p=0.039), at test of cure (21 days), and last follow-up (42 days). In patients with documented infections, the rate of microbiological eradication was similar in both groups. Drug-related adverse events that led to drug discontinuation was similar in both groups (7%). Similarly overall mortality was similar in both groups.ConclusionThe empiric use of C/T to cover gram negative organisms in high risk febrile neutropenic patients with hematological malignancies is safe and associated with better clinical outcome than SOC antimicrobial agents. The emergence of resistant pathogens should be further evaluated.Disclosures Issam I. Raad, MD, Citius (Other Financial or Material Support, Ownership interest)Cook Medical (Grant/Research Support)Inventive Protocol (Other Financial or Material Support, Ownership interest)Novel Anti-Infective Technologies (Shareholder, Other Financial or Material Support, Ownership interest)

167. A Phase 1b, Randomized, Double-blind, Placebo-controlled, Multiple-ascending Dose Study to Investigate the Safety, Tolerability, and Pharmacokinetics of DSTA4637S in Patients with staphylococcus Aureus Bacteremia Receiving Standard-of-care Antibiotics

BackgroundNew treatment approaches for complicated Staphylococcus aureus bacteremia (SAB) are needed. DSTA4637S is a THIOMABTM antibody-antibiotic conjugate consisting of an engineered human IgG1 monoclonal antibody that binds to wall teichoic acid at the surface of S. aureus, a protease-cleavable linker, and a novel rifamycin class antibiotic, dmDNA31. This Phase 1b study assessed the safety, tolerability, and pharmacokinetics of DSTA4637S in patients with complicated SAB.MethodsMulticenter, double-blind, placebo controlled, multiple-ascending dose clinical trial. Patients 18–79 years old with complicated SAB requiring at least 4 weeks of IV anti-staphylococcal standard-of-care (SOC) antibiotics were randomized to receive 4–6 doses of 15, 45, and 100 mg/kg IV DSTA4637S or placebo (6 active:2 placebo) every 7 days in combination with SOC antibiotics. Patients needed ≥ 1 blood culture positive for S. aureus collected within 120 hours prior to randomization. Patients were followed for 120 days after the end of treatment.ResultsTwenty-five patients with complicated SAB (bone & joint, n=14; endocarditis, n=5; other endovascular, n=5; pneumonia, n=1) were randomized and received 1–6 doses of study drug (19 active:6 placebo). Nine patients (36%) had MRSA. Ten patients completed ≥4 doses of DSTA4637S. The most common treatment-related adverse events were infusion-related reactions (IRRs) (5/19), and abnormal serum color (5/19)/skin discoloration (3/19 (due to dmDNA31). IRRs were not dose-dependent and were reversible with supportive care. Ten of 19 patients (40%) discontinued study drug (9 DSTA4637S,1 placebo); 4/19 (21%) due to IRR. DSTA4637S recipients showed no dose-related changes in laboratory values or vital signs vs. placebo. Observed exposures (Cmax and AUC) were lower in patients immediately after dosing compared to a prior study in healthy volunteers; minimal accumulation occurred. No obvious trends in exploratory bacterial and inflammatory biomarkers were observed between treatment groups.ConclusionDSTA4637S in patients with complicated SAB demonstrated increased IRRs and decreased exposure compared to healthy volunteers, highlighting the importance of Phase I studies of novel treatments in infected SAB patients and not simply healthy controls.DisclosuresJeremy Lim, PharmD, Roche (Employee, Shareholder) Nicholas Lewin-Koh, PhD, Genentech (Employee) Tom Chu, MD, PhD, Genentech (Employee) Sharon M. Rymut, PhD, Genentech (Employee, Shareholder) Aklile Berhanu, PhD, Genentech, Inc. (Employee, Equity interest (Stock/Stock Options)) Montserrat Carrasco-Triguero, PhD, Genentech (Employee) Carrie C. Rosenberger, PhD, Genentech (Employee, Shareholder) Wouter L. Hazenbos, PhD, Genentech (Employee) Loren G. Miller, MD, MPH, genentech (Grant/Research Support) Vance G. Fowler, Jr., MD, MHS, Achaogen (Consultant)Actavis (Grant/Research Support)Advanced Liquid Logics (Grant/Research Support)Affinergy (Consultant, Research Grant or Support)Affinium (Consultant)Allergan (Grant/Research Support)Ampliphi Biosciences (Consultant)Basilea (Consultant, Research Grant or Support)Bayer (Consultant)C3J (Consultant)Cerexa (Consultant, Research Grant or Support)Contrafect (Consultant, Research Grant or Support)Cubist (Grant/Research Support)Debiopharm (Consultant)Destiny (Consultant)Durata (Consultant)Forest (Grant/Research Support)Genentech (Consultant, Research Grant or Support)Integrated Biotherapeutics (Consultant)Janssen (Consultant, Research Grant or Support)Karius (Grant/Research Support)Locus (Grant/Research Support)Medical Biosurfaces (Grant/Research Support)Medicines Co. (Consultant)Medimmune (Consultant, Research Grant or Support)Merck (Consultant, Research Grant or Support)NIH (Grant/Research Support)Novadigm (Consultant)Novartis (Consultant, Research Grant or Support)Pfizer (Grant/Research Support)Regeneron (Consultant, Research Grant or Support)Tetraphase (Consultant)Theravance (Consultant, Research Grant or Support)Trius (Consultant)xBiotech (Consultant) Jose M Miro, MD PhD, GENENTECH (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member) Jessica A. Couch, PhD, Genentech (Employee, Shareholder) Melicent C. Peck, MD, PhD, Genentech (Employee)

The limitations of mono- and combination antibiotic therapies on immature biofilms in a murine model of implant-associated osteomyelitis.

Treatment of implant-associated orthopedic infections remains challenging, partly because antimicrobial treatment is ineffective after a mature biofilm covers the implant surface. Currently, the relative efficacy of systemic mono- and combination standard-of-care (SOC) antibiotic therapies over the course of mature biofilm formation is unknown. Thus, we assessed the effects of cefazoline (CEZ), gentamicin (GM), and vancomycin, with or without rifampin (RFP), on Staphylococcus aureus biofilm formation during the establishment of implant-associated osteomyelitis in a murine tibia model. Quantitative scanning electron microscopy of the implants harvested on Days 0, 3, and 7 revealed that all treatments except CEZ monotherapy significantly reduced biofilm formation when antibiotics started at Day 0 (0.46- to 0.25-fold; p < 0.05). When antibiotics commenced 3 days after the infection, only GM monotherapy significantly inhibited biofilm growth (0.63-fold; p < 0.05), while all antibiotics inhibited biofilm formation in combination with RFP (0.56- to 0.44-fold; p < 0.05). However, no treatment was effective when antibiotics commenced on Day 7. To confirm these findings, we assessed bacterial load via colony-forming unit and histology. The results showed that GM monotherapy and all combination therapies reduced the colony-forming unit in the implant (0.41- to 0.23-fold; p < 0.05); all treatments except CEZ monotherapy reduced the colony-forming unit and staphylococcus abscess communities in the tibiae (0.40- to 0.10-fold; p < 0.05). Collectively, these findings demonstrate that systemic SOC antibiotics can inhibit biofilm formation within 3 days but not after 7 days of infection. The efficacy of SOC monotherapies, CEZ particularly, is very limited. Thus, combination treatment with RFP may be necessary to inhibit implant-associated osteomyelitis.

PIN142 High Cost of Treatment with NOVEL Antibiotics Compared to Standard of Care in Two EU Markets: Time for Subscription-Based Pricing?

Many novel antibiotics are intended to be effective against pathogens resistant to Standard of Care (SoC) antibiotics and attenuate progress of antimicrobial resistance. This study investigates the cost of novel antibiotics in UK and Germany compared to generic SoC and discusses opportunities that may remove barriers to use and offer increased value. Approved systemic IV and oral antibiotics (01/2010 – 06/2020) were extracted from the EMA website and pricing databases were reviewed to identify respective ex-manufacturer list prices in the UK and Germany. Antibiotics not commercially available/without publicly available pricing were excluded. Qualitative semi-structured interviews (n=10) were conducted with UK and Germany key clinical stakeholders to review the impact of price on utilization. Data for 9 novel antibiotics were analysed. 3 were approved for use in gram-negative infections, 5 in gram-positive, and 1 in gram-positive/negative. Cost of treatment with novel antibiotics (drug cost) compared to SoC antibiotics was on average 5X higher (range 1.4X – 16.2X). All novel antibiotics listed were restricted to 2nd or 3rd line use (once causative pathogen has been suspected/established). Respondents noted that cost is one of the key reasons novel antibiotics are restricted to 2nd or 3rd line use. In addition, they noted that the real-life value of novel antibiotics compared to SoC is more difficult to establish whilst their use is restricted to patients who have failed several therapies, often with complicated infections. As clinical experience increases, using these therapies in earlier lines where their comparative effectiveness against resistant pathogens can be better evaluated - as well as their benefit towards antimicrobial resistance stewardship - would help to demonstrate value. A subscription-based pricing structure may be one option to facilitate this.

Real-world Experience of Bezlotoxumab for Prevention of Clostridioides difficile Infection: A Retrospective Multicenter Cohort Study.

BackgroundBezlotoxumab is approved for prevention of recurrence of Clostridioides difficile infection (CDI) in adults receiving standard of care (SoC) therapy based on findings from MODIFY clinical trials. However, utilization practices and validation of trial results in the real world are limited.MethodsRecords of patients receiving bezlotoxumab between April 2017 and December 2018 across 34 infusion centers in the United States were retrospectively reviewed. Recurrent CDI (rCDI), defined as diarrhea lasting ≥2 days resulting in treatment, was assessed 90 days postbezlotoxumab.ResultsThe study cohort included 200 patients (median age, 70 years; 66% female; median Charlson comorbidity index, 5), of whom 86% (n = 173) had prior CDI episodes and 79% (n = 158) had ≥2 risk factors for rCDI. SoC antibiotics included vancomycin (n = 137, 68%), fidaxomicin (n = 60, 30%), and metronidazole (n = 3, 2%). Median time from C. difficile stool test to bezlotoxumab and initiation of SoC to bezlotoxumab were 15 days and 11 days, respectively. Within 90 days, 31 of 195 patients (15.9%) experienced rCDI, which corresponds to a success rate of 84.1%. Patients with ≥2 CDI recurrences prebezlotoxumab had a higher risk of subsequent rCDI compared with those with 1 recurrence or primary CDI (hazard ratio, 2.77; 95% confidence interval, 1.14–6.76; P = .025).ConclusionsThis real-world multicenter study demonstrated successful prevention of rCDI with bezlotoxumab comparable to clinical trial results regardless of type of SoC and timing of infusion. Multiple prior CDI recurrences were associated with a higher risk of subsequent rCDI, supporting the use of bezlotoxumab earlier in the disease course.

Gram-Negative Bacterial Lysins.

Antibiotics have had a profound impact on human society by enabling the eradication of otherwise deadly infections. Unfortunately, antibiotic use and overuse has led to the rapid spread of acquired antibiotic resistance, creating a major threat to public health. Novel therapeutic agents called bacteriophage endolysins (lysins) provide a solution to the worldwide epidemic of antibiotic resistance. Lysins are a class of enzymes produced by bacteriophages during the lytic cycle, which are capable of cleaving bonds in the bacterial cell wall, resulting in the death of the bacteria within seconds after contact. Through evolutionary selection of the phage progeny to be released and spread, these lysins target different critical components in the cell wall, making resistance to these molecules orders of magnitude less likely than conventional antibiotics. Such properties make lysins uniquely suitable for the treatment of multidrug resistant bacterial pathogens. Lysins, either naturally occurring or engineered, have the potential of being developed into fast-acting, narrow-spectrum, biofilm-disrupting antimicrobials that act synergistically with standard of care antibiotics. This review focuses on newly discovered classes of Gram-negative lysins with emphasis on prototypical enzymes that have been evaluated for efficacy against the major antibiotic resistant organisms causing nosocomial infections.

IMPACT-TB*: A Phase II Trial Assessing the Capacity of Low Dose Imatinib to Induce Myelopoiesis and Enhance Host Anti-Microbial Immunity Against Tuberculosis. *Imatinib Mesylate per Oral As a Clinical Therapeutic for TB

Background: With existing anti-tubercular therapies, treatment success rates for multi- and extensively-drug resistant tuberculosis (MDR-TB, XDR-TB) are dismal, highlighting the urgent need for new drugs. Ratios of myeloid to lymphoid cells are important predictors of TB disease susceptibility and vaccine efficacy. Imatinib mesylate (Gleevec), a cancer drug used in humans for chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors (GISTs), is a potential "host- directed therapeutic (HDT)" for drug resistant TB infections and HIV/TB co-infections. Imatinib inhibits c-Abl tyrosine kinase (TK), which is dysregulated in CML, as well as related TKs (e.g. c-Kit). Imatinib facilitates clearance of Mycobacterium tuberculosis (Mtb), by disrupting the cellular mechanisms that Mtb uses for entry and survival in host cells. At doses 10-fold lower than those used for CML, imatinib also stimulates "emergency hematopoiesis," a host immune response to infection that mobilizes myeloid cell differentiation in the bone marrow and alters ratios of myeloid to lymphoid cells in the periphery towards protective levels, an effect suppressed by Mtb. Imatinib acts synergistically with antibiotics and is effective against antibiotic-resistant mycobacteria, and may be less likely to engender resistance compared to antibiotics. Preclinical data at low doses indicate efficacy of imatinib in a non-human primate (NHP) model of infection with TB or, alternatively, TB/SIV, which mimics poorly controlled TB or HIV/TB in humans. Study Design, Endpoints, and statistical design: We describe the design of two NIH-sponsored Phase II clinical trials in humans (NCT03891901). The first trial will comprise testing of 4 low doses of imatinib with or without antibiotics in 72 normal individuals in the United States. We will determine safety, immunological responses, and drug-drug interactions with standard of care antibiotics. The primary endpoints are to (i) identify the two best doses that induce myelopoiesis in humans, (ii) maximize bactericidal activity by immune cells ex vivo, and (iii) maximize safety. The trial is powered to detect a 2-fold increase in myelopoiesis across all imatinib doses relative to untreated individuals. The second trial will assess the safety and microbiologic efficacy of two doses of imatinib administered over 3 months in conjunction with optimized background antibiotic regimens versus the optimized background regimen alone. The trial will include 180 individuals with TB or HIV/TB in South Africa (60 per arm). The primary endpoints are (i) the time to sputum culture conversion, (ii) lung function by PET-CT and spirometry, and (iii) immunological parameters associated with myelopoieisis. Secondary endpoints include transcriptomics, proteomics, and measures of pathogen-specific immune responses. The trial is powered to detect a 2-fold increase in myelopoiesis across all imatinib doses relative to untreated individuals. The trial is statistically powered to distinguish at either dose an improvement over baseline treatment in time to sputum conversion or lung function or both. Major Inclusion/Exclusion Criteria: Phase II dosing trial: Normal volunteers, age 18 - 55 years. Phase II efficacy trial: Active antibiotic-sensitive tuberculosis with or without HIV. Pregnant women are excluded from both studies. Trial Status : The dosing trial has FDA and NIAID approval to begin and is currently undergoing registration with DAIDS prior to starting enrollment. Overall Goal: Data from these trials will provide a paradigm with which to further evaluate imatinib or other immunomodulatory HDTs as therapeutics for TB infection and HIV/TB co-infection. If successful, imatinib may shorten the time of treatment and limit development of antibiotic resistance, and may be useful against antibiotic resistant strains. This project is supported a grant from NIH/NIAID. Disclosures Waller: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Other: Travel expenses, Research Funding; Cerus Corporation: Other: Stock, Patents &amp; Royalties; Chimerix: Other: Stock; Cambium Oncology: Patents &amp; Royalties: Patents, royalties or other intellectual property ; Amgen: Consultancy; Kalytera: Consultancy. OffLabel Disclosure: Imatinib is known as a therapeutic for CML. Here, we will discuss our plans to develop imatinib as a host-directed-therapy to improve treatment of multi-drug-resistant tuberculosis

LB3. Exebacase (EXE) Reduced Length of Stay and 30-Day Readmission Rates for US Patients with Methicillin-Resistant Staphylococcus aureus (MRSA) Bacteremia Including Endocarditis Compared with Standard of Care Antibiotics (SoC) Alone in a Phase 2 Study

BackgroundExebacase, a lysin (cell wall hydrolase), is the first direct lytic agent to report Phase 2 study results in Staphylococcus aureus bacteremia including endocarditis. Among MRSA patients enrolled in this randomized, double-blind, placebo, controlled study, EXE used in addition to standard of care antibiotics (SoC), had 42.8% higher clinical responder rates (CRRs) compared SoC alone. We sought to determine whether these differences in CRRs translated into reductions in health resource utilization (HRU) in this population of critically ill, hospitalized patients.MethodsThe microbiological intent-to-treat population included 116 patients (71 EXE, 45 SoC) with documented S. aureus who received a single 2-hour infusion of blinded study drug dosed based on target attainment. The primary efficacy endpoint was CRR at Day 14. Diagnoses and clinical outcomes were determined by a blinded Adjudication Committee. HRU including length of stay (LOS), and 30-day hospital readmission rates (HRR) for all causes (AC) and for S. aureus (SA) were evaluated in MRSA patients who were alive at the time of discharge.ResultsThe average patient was white, male and ~56 years old (67.8%). Twenty-seven EXe patients (38.0%) and 16 SoC patients (35.6%) had MRSA. All but 2 MRSA patients (1 EXE, 1 SoC) were enrolled in the United States. The Day 14 CRR were 70.4% for EXE and 60.0% for SoC groups (p=0.314) overall. In a prespecified analysis of MRSA patients, the CRR with EXE was 74.1% vs. 31.3% with SoC (P = 0.010). Among MRSA patients who received study drug, incidence of treatment emergent adverse events (TEAEs) was balanced between groups (24 (88.9%) in EXE and 15 (98.3%) in SoC) as were serious TEAEs (17(63.0%) in EXE, 12 (75%) in SoC). 1 EXE and 2 SoC US MRSA patients died in hospital. Among US MRSA patients discharged alive from the hospital, the median LOS after study drug was 6 vs. 10 days for EXE and SoC, respectively. Thirty-day AC HRR were 16% vs. 30.8%, for EXE vs. SoC, respectively, and 30-day SA HRR were 8% vs. 15.4%, respectively.ConclusionsExebacase used in addition to SoC was associated with a reduction in length of hospital stay and 30-day readmission rates for all causes and for S. aureus compared with SoC alone in patients being treated for MRSA bacteremia/endocarditis.DisclosuresCara Cassino, MD, ContraFect Corporation (Employee), Hemal Shah, PharmD, Boehringer Ingelheim (Consultant), ContraFect Corp (Consultant), DBV Technologies (Consultant), Mylan specialty (Consultant), Nabriva (Consultant), Joy Lipka-Diamond, MS, ContraFect Corporation (Consultant), Anita F. Das, PhD, Achaogen (Consultant), AntiobioTx (Consultant), Boston Pharmaceuticals (Consultant), Cempra (Consultant), ContraFect Corporation (Consultant), Iterum Therapeutics (Consultant), Nabriva (Consultant), Paratek (Consultant), Tetraphase (Consultant), UTILITY (Consultant), Wockhardt (Consultant).

711. Exebacase (Lysin CF-301) Activity Against Staphylococcus aureus (S. aureus) Isolates From Bacteremic Patients Enrolled in a Phase 2 Study (CF-301-102)

BackgroundExebacase (CF-301) is a novel, recombinantly-produced, bacteriophage-derived lysin (cell wall hydrolase) which is the first lysin to report Phase 2 (Ph2) results which demonstrated 42.8% higher clinical responder rates with a single dose of exebacase used in addition to standard of care antibiotics (SOC) vs. SOC alone for the treatment of methicillin-resistant S. aureus (MRSA) bacteremia including endocarditis. We examined exebacase activity by broth microdilution (BMD) against baseline methicillin-sensitive S. aureus (MSSA) and MRSA isolates from each of the 116 participants in the recently complete exebacase”first in-patient’ Ph2 study (NCT03163446).MethodsPatients with complicated bacteremia or endocarditis caused by S. aureus were enrolled into Study CF-301-102 at study centers in the United States, EU, Latin America, Israel, and Russia from 2017 and 2018. Baseline isolates from blood cultures were collected prior to administration of exebacase. Exebacase MICs against 117 isolates of MSSA (n = 74) and MRSA (n = 43) were determined at a central laboratory using a modified BMD approved by the CLSI for exebacase AST.ResultsThe exebacase MICs of baseline patient isolates from the Ph2 study ranged from 0.125 – 2 µg/mL and the MIC50/90 values for all MSSA and MRSA isolates were 0.5/1 µg/mL. Exebacase MICs reported in a recent surveillance study were similar, with MIC50/90 values of 0.5/1 µg/mL. Of the 6 total subjects with EXE MICs of 2, 3 were clinical responders, 2 were indeterminate (not available for assessment), and 1 was a clinical nonresponder at Day 14.ConclusionExebacase was highly active against all baseline S. aureus isolates from blood cultures obtained from bacteremic patients enrolled in the Ph2 study. Based on data from previously presented exposure target attainment animal studies, PK/PD modeling and preliminary nonclinical breakpoint assessments, we expected that strains with MIC values of ≤2 µg/mL will have been susceptible to the Ph2 clinical exebacase dose determined based on target attainment studies under study in Ph2.Disclosures All authors: No reported disclosures.

460. Ceftriaxone vs. Standard of Care for Definitive Treatment of Methicillin-Susceptible Staphylococcus aureus Infections

Backgroundβ-Lactam antibiotics, specifically nafcillin, oxacillin, and cefazolin, have proven efficacy for methicillin-susceptible Staphylococcus aureus (MSSA) infections. Outpatient antimicrobial therapy (OPAT) with these agents is limited due to side effects and multiple doses required per day. Ceftriaxone, a third-generation cephalosporin, has a favorable profile for OPAT. Limited evidence supporting ceftriaxone therapy for MSSA infections prevents its widespread use.MethodsA multi-center, retrospective cohort study comparing patients who received cefazolin or nafcillin to patients who received ceftriaxone for treatment of microbiologically proven MSSA infections was conducted from February 2016 to February 2018. The primary outcome of interest was a clinical success, defined as the absence of infection-related readmission, worsening infection, or recurrent infection within 90 days. Secondary outcomes included the rate of adverse reactions, length of stay, and impact of Infectious Diseases (ID) consult.Results66 patients treated with ceftriaxone and 156 patients treated with cefazolin or nafcillin were included. Skin and soft tissue and bone and joint were the most common infections in the ceftriaxone group, whereas bacteremia was most common in the nafcillin and cefazolin group. There were significant differences in baseline age (61 years vs. 59 years; P = 0.036) and intravenous drug use (1 patient vs. 25 patients; P = 0.002) between groups. As shown in Table 1, there were significantly lower rates of clinical success with ceftriaxone compared with standard of care as a composite of all infection sites (78.8% vs. 91%; P = 0.012). No statistically significant differences were seen in safety outcomes or ID consultation. Length of stay was significantly longer in the nafcillin and cefazolin group (5.2 days vs. 12.8 days; P ≤ 0.0001).ConclusionThe results of this study indicate that patients treated with ceftriaxone for MSSA infections had significantly lower rates of clinical success compared with standard of care antibiotics. Nafcillin or cefazolin should remain as first-line agents for treatment of bone and joint infections and skin and soft-tissue infections due to MSSA. Disclosures All authors: No reported disclosures.

The NAP1 Strain of Clostridium difficile Is Strongly Associated With Fecal Microbiota Transplant Failure: A Large Retrospective Study

Introduction: Multiply recurrent Clostridium difficile infection (mrCDI) incidence increased from 2001-2012 along with an increasing prevalence of the NAP1 strain of C. difficile. NAP1 genotype positivity is reported to be associated with failure of standard of care (SOC) antibiotic therapy. Fecal microbiota transplant (FMT) is more effective for treatment of mrCDI than SOC antibiotics, however FMT for mrCDI still has a 10-20% failure rate; the source of which is not fully understood. Even though NAP1 positivity is an established risk factor for antibiotic treatment failure, NAP1 genotype testing is not widely performed. Data on the effect of NAP1 positive strains in patients with mrCDI undergoing FMT is lacking. Our institution sees referrals from hospitals which test for NAP1. We hypothesized that NAP1 strain positivity would be associated with FMT failure in patients being treated for mrCDI. Methods: Retrospective cohort study at an academic tertiary medical center of all patients with mrCDI who underwent outpatient FMT for the first time between 2014 and 2018. Pre-FMT variables included: NAP1 genotype, demographics, comorbidities, and pre-FMT antibiotic therapy. NAP1 genotype result was determined based on the most proximal positive C. difficile result that then prompted FMT therapy. Primary endpoint was failure of FMT, defined as recurrent diarrhea with positive lab confirmation of C. difficle within 12 weeks after FMT. Data analyzed using SPSS software, utilizing chi squared and Student’s t-tests. Results: There were 144 patients who underwent an initial FMT for mrCDI, with an overall failure rate of 11.8% (17/144). Of those 144 patients, 76 (52%) had NAP1 genotype testing, and 34.2% of those tested (26/76) were NAP1 positive. The FMT failure rate in all patients tested for NAP1 was 15.7% (12/76). The FMT failure rate in NAP1 positive patients was 38.4% (10/26) versus 4.0% (2/50) in NAP1 negative patients, and was significantly different [X2 (1, N=76)=15.27; p<0.0001]. The relative risk (RR) of FMT failure in NAP1 positive patients was 9.62 (95% CI: 2.27 - 40.68). Among just those patients who were NAP1 positive, there was no risk factor associated with failed FMT. Conclusion: This is the first study to show the NAP1 strain of mrCDI to be strongly associated with FMT failure. C. difficile strain type may play a role in an evolving understanding of why FMT fails, and could provide predictive clinical information for patients and providers. A well designed prospective study is indicated.111_A Figure 1. Comorbidities and risk factors among patients tested for NAP1, based on successful or failed FMT procedures. The NAP1 positive genotype was significantly more likely in failed FMT procedures than in successful FMTs111_B Figure 2. 2x2 contingency table breaking down the distribution of the 76 patients who had NAP1 testing performed on their C. difficile sample.

Application of Antibody-Mediated Therapy for Treatment and Prevention of Clostridium difficile Infection.

Clostridium difficile causes antibiotic- and healthcare-associated diarrhea, which is characterized by a high mortality rate (5–15%) and high recurrence rate of 20% or more. Therapeutic alternatives to antibiotics are urgently needed to improve the overall cure rate. Among these, therapeutic antibodies have shown promising results in clinical studies. Herein, the authors review current monoclonal and polyclonal anti- C. difficile antibodies that have entered the clinical development stage, either for systemic administration or by the oral route. The antibodies can be applied as monotherapy or in combination with standard-of-care to treat an infection with C. difficile or to protect from a recurrence. Bezlotoxumab is the first antibody for secondary prevention of recurrence of C. difficile infection approved by the regulatory agencies in US and Europe. The human monoclonal antibody is administered systemically to patients receiving oral standard-of–care antibiotics. Other antibodies are currently in the clinical pipeline, and some are intended for oral use. They show a good safety profile, high efficacy and low production costs, and can be considered promising therapies of the future. The most promising orally administered drug candidate is a bovine antibody from hyperimmune colostral milk, which is in an advanced clinical development stage. Which antibody will enter the market is dependent on its bioavailability at the site of infection as well as its activity against C. difficile toxins, protection against colonization and possible action on spore formation. The antibody must demonstrate a clear benefit in comparison with other available treatment options to be considered for use by clinicians.

Restoration of sensitivity of a diverse set of drug-resistant Staphylococcus clinical strains by bactericidal protein P128.

P128, a phage-derived lysin, exerts antibacterial activity on staphylococci by cleaving the pentaglycine-bridge of peptidoglycan. We sought to determine whether the presence of P128 could re-sensitize drug-resistant bacteria to antibiotics by virtue of its cell wall degrading property. P128 was tested in combination with standard-of-care (SoC) drugs by chequerboard assays on planktonic cells and biofilms of strains individually resistant to these drugs. The bactericidal effect of P128 and drug combinations on planktonic cells and biofilms was measured by c.f.u. reduction assays. A mouse model of MRSA bacteraemia was used to test the efficacy of P128 and oxacillin in combination. A combination of sub-MIC P128 (0.025-0.20 µg ml-1) and 0.5 µg ml-1 of oxacillin resulted in inhibition of bacterial growth in four MRSA strains. Similar results were seen with all the other drugs tested, wherein sub-MIC of P128 re-sensitized S. aureus and CoNS strains to SoC drugs. The chequerboard assays on strains of S. aureus and CoNS showed that combinations of P128 and antibiotics consistently inhibited bacterial growth on biofilms. Data from scanning electron microscopy and c.f.u. reduction assays on drug-resistant S. aureus and CoNS demonstrated that sub-MICs of P128 and SoC antibiotics could kill biofilm-embedded bacteria. In vivo, a combination of sub-therapeutic doses of P128 and oxacillin could help protect animals from fatal bacteraemia. The ability of P128 to re-sensitize bacteria to SoC drugs suggests that combinations of P128 and SoC antibiotics can potentially be developed to treat infections caused by drug-resistant strains of staphylococci.

Bezlotoxumab (BEZ) for Prevention of Clostridium Difficile Infection (CDI) Recurrence (rCDI): Outcomes in Patients with Substantial Renal Impairment (SRI)

BackgroundCDI in patients with SRI is harder to treat and is associated with higher recurrence. MODIFY I/II found that BEZ, a monoclonal antibody against C. difficile toxin B, is superior to placebo (PBO) at preventing rCDI in patients receiving standard of care antibiotics (SoC). This post hoc analysis assessed efficacy of BEZ in patients with SRI in the MODIFY studies.MethodsMODIFY I/II mITT populations were pooled to estimate initial clinical cure (ICC), rCDI, and mortality through 12 weeks. Estimated glomerular filtration rate (eGFR) was calculated with the Modified Diet in Renal Disease (MDRD) method. SRI was defined as eGFR <60 mL/minute/1.73 m2. ICC was defined as SOC ≤16 days and no diarrhea on the 2 days after SoC end. rCDI was defined as diarrhea and toxigenic C. difficile in stool. Mortality within 90 days after randomization was summarized.ResultsOf the included 1554 patients, 1101 had no SRI (≥90: n = 612; 60 to < 90: n = 489); 430 had SRI (30 to <60: n = 290; 15 to <30: n = 71; <15: n = 69); 23 had unknown eGFR. 87% of SRI patients had ≥1 risk factor for rCDI. Relative to patients without SRI, more patients with SRI were ≥65 years (69% vs. 44%), immunocompromised (25 vs. 20%), had ribotype 027 (25% vs. 17%), and used concomitant antibiotics during SoC (41% vs. 31%) or after SoC (36% vs. 28%). SRI patients had more severe CDI (21% vs. 14%), lower CDI cure (78.4% vs. 80.1%), higher rCDI (31.6% vs. 27.8%), and death (11.6% vs. 5.3%) In the SRI cohort, more BEZ vs. PBO patients were inpatients (81% vs. 72%), ≥65 years (72% vs. 65%), immunocompromised (28 vs. 22%), and used systemic antibiotics after SoC ended (40% vs. 32%). The rate of ICC was similar between treatment groups and the rCDI rate was significantly less the BEZ vs. PBO group (Table).ConclusionSRI was associated with worse CDI outcomes. BEZ given with SoC significantly reduced rCDI in patients with SRI and could benefit this hard to treat population.Disclosures Y. Golan, Merck & Co., Inc.: Grant Investigator, Scientific Advisor and Speaker’s Bureau, Research support and Speaker honorarium; Pfizer: Scientific Advisor, Speaker honorarium; Allergab: Grant Investigator and Scientific Advisor, Research grant and Speaker honorarium; The Medicines Company: Scientific Advisor, Speaker honorarium; Seres Pharmaceuticals: Scientific Advisor, Speaker honorarium; H. L. DuPont, BioK International, Salix: Consultant, Consulting fee; University Rebiotix, Seres, Takeda: Grant Investigator, Grant recipient; F. Aldomiro, BMS & ViiV: Scientific Advisor, Consulting fee; MSD, Viiv, Astellas & Pfizer: Participated in Clinical Trials, Research support; E. H. Jensen, Merck & Co., Inc.: Employee, may own stock/hold stock options in Company; M. E. Hanson, Merck & Co. Inc.: Employee, may own stock/hold stock options in the Company; M. B. Dorr, Merck & Co., Inc.: Employee and Shareholder, may own stock/hold stock options in the Company

Bezlotoxumab: anti-toxin B monoclonal antibody to prevent recurrence of Clostridium difficile infection

ABSTRACTIntroduction: Clostridium difficile infection (CDI) is the most common nosocomial infection in the U.S. 25% of CDI patients go on to develop recurrent CDI (rCDI) following current standard of care (SOC) therapy, leading to morbidity, mortality and economic loss. The first passive immunotherapy drug targeting C.difficile toxin B (bezlotoxumab) has been approved recently by the FDA and EMA for prevention of rCDI.Areas covered: A body of key studies was selected and reviewed by the authors. The unmet needs in CDI care were ascertained with emphasis in rCDI, including the epidemiology, pathophysiology and current management. The current knowledge about the immune response to C. difficile toxins and how this knowledge led to the development and the clinical use of bezlotoxumab is described. Current and potential future competitors to the drug were examined.Expert commentary: A single 10 mg/kg intravenous infusion of bezlotoxumab has been shown to decrease rCDI by ~40% (absolute reduction ~10%) in patients being treated for primary CDI or rCDI with SOC antibiotics. Targeting C.difficile toxins by passive immunotherapy is a novel mechanism for prevention of C.difficile infection. Bezlotoxumab will be a valuable adjunctive therapy to reduce the burden of CDI.

Bezlotoxumab: Could This be the Answer for Clostridium difficile Recurrence?

To review the pharmacology, pharmacokinetics, efficacy, safety, and place in therapy of bezlotoxumab (BEZ), a novel monoclonal antibody against Clostridium difficile toxin B. A PubMed search was conducted for data between 1946 and April 2017 using MeSH terms bezlotoxumab, MK-6072, or MDX-1388 alone and the terms Clostridium difficile combined with monoclonal antibody or antitoxin. The literature search was limited to English-language studies that described clinical efficacy, safety, and pharmacokinetics in humans and animals. Abstracts featuring prepublished data were also evaluated for inclusion. BEZ is indicated for adult patients receiving standard-of-care (SoC) antibiotics for C difficile infection (CDI) to prevent future recurrence. Two phase III trials-MODIFY I (n = 1452) and MODIFY II (n = 1203)-demonstrated a 40% relative reduction in recurrent CDI (rCDI) with BEZ compared with placebo (16.5% vs 26.6%, P < 0.0001). The most common adverse drug events associated with BEZ were mild to moderate infusion-related reactions (10.3%). In patients treated with SoC antibiotics, BEZ is effective in decreasing rCDI. BEZ has no apparent effect on treatment of an initial CDI episode. In light of increasing rates of CDI, BEZ is a promising option for preventing recurrent episodes. The greatest benefit has been demonstrated in high-risk patients, though the targeted patient population is yet to be defined.

Cost-effectiveness of ceftolozane/tazobactam compared with piperacillin/tazobactam as empiric therapy based on the in-vitro surveillance of bacterial isolates in the United States for the treatment of complicated urinary tract infections

BackgroundA challenge in the empiric treatment of complicated urinary tract infection (cUTI) is identifying the initial appropriate antibiotic therapy (IAAT), which is associated with reduced length of stay and mortality compared with initial inappropriate antibiotic therapy (IIAT). We evaluated the cost-effectiveness of ceftolozane/tazobactam compared with piperacillin/tazobactam (one of the standard of care antibiotics), for the treatment of hospitalized patients with cUTI.MethodsA decision-analytic Monte Carlo simulation model was developed to compare the costs and effectiveness of empiric treatment with either ceftolozane/tazobactam or piperacillin/tazobactam in hospitalized adult patients with cUTI infected with Gram-negative pathogens in the US. The model applies the baseline prevalence of resistance as reported by national in-vitro surveillance data.ResultsIn a cohort of 1000 patients, treatment with ceftolozane/tazobactam resulted in higher total costs compared with piperacillin/tazobactam ($36,413 /patient vs. $36,028/patient, respectively), greater quality-adjusted life years (QALYs) (9.19/patient vs. 9.13/patient, respectively) and an incremental cost-effectiveness ratio (ICER) of $6128/QALY. Ceftolozane/tazobactam remained cost-effective at a willingness to pay of $100,000 per QALY compared to piperacillin/tazobactam over a range of input parameter values during one-way and probabilistic sensitivity analysis.ConclusionsModel results show that ceftolozane/tazobactam is likely to be cost-effective compared with piperacillin/tazobactam for the empiric treatment of hospitalized cUTI patients in the United States.

Synergistic activity profile of an antimicrobial peptide against multidrug-resistant and extensively drug-resistant strains of Gram-negative bacterial pathogens.

Infection sustained by multidrug-resistant and extensively drug-resistant bacterial pathogens is often untreatable with the standard of care antibiotics, and the combination of anti-infective compounds often represents the only therapeutic strategy to face this major clinical treat. SET-M33 is a novel antimicrobial peptide (AMP) that has demonstrated in vitro and in vivo antimicrobial activity against Gram-negative bacteria and has shown interesting features in preclinical evaluations. Particularly, it showed efficacy against a number of multidrug-resistant and extensively drug-resistant clinical strains of Gram-negative pathogens, in in vitro and in vivo assessments. Here, we explored the potential synergistic activity of SET-M33 in combination with different standard of care antibiotics by the checkerboard method against a panel of six strains of Gram-negative pathogens including multidrug-resistant and extensively drug-resistant Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. SET-M33 showed synergistic activity with antibiotics of different families against these clinically relevant strains. A synergistic effect was observed for SET-M33 in combination with rifampin, meropenem, aztreonam, and tobramycin mostly on K.pneumoniae and A.baumannii strains, while the SET-M33 plus ciprofloxacin combination was additive with all tested strains. Synergy was not apparently linked to the bacterial species or phenotype but was rather strain-specific, highlighting the need for individual strain testing for synergistic antimicrobial combinations. These findings extend current knowledge on synergistic activity of AMPs in combination with conventional agents and support the potential role of SET-M33 as a novel therapeutic agent against antibiotic-resistant Gram-negative pathogens. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.

New and emerging therapies for Clostridium difficile infection.

Clostridium difficile infection has attained high prominence given its prevalence and impacts on patients and healthcare institutions. Multiple new approaches to the prevention and treatment of C. difficile infection (CDI) are undergoing clinical trials. Bezlotoxumab is a monoclonal antibody against toxin B that has successfully completed phase III studies, demonstrating a significant reduction in recurrent CDI when given with standard of care antibiotics. Antibiotics under development include cadazolid and ridinilazole, whereas surotomycin has had disappointing phase III results. Multiple live biotherapeutics are being developed, including freeze thawed and encapsulated versions of faecal microbiota transplantation to improve the practicality of treating patients with recurrent CDI. Alternatives to faecal microbiota transplantation, that aim to improve safety, including a microbial suspension, RBX2660, and a complex spore formulation, SER-109, have progressed to phase II studies. A nontoxigenic C. difficile strain has also shown promise to prevent recurrent CDI. In addition, three C. difficile vaccines have progressed to phase II/III clinical trials. The diverse approaches to treating and preventing CDI offer substantial promise that new treatment options will soon emerge, particular ones that reduce the risk of recurrences.