Bacteriophage and antibiotic combination therapy for recurrent Enterococcus faecium bacteremia.

Enterococcus faecium is a member of the human gastrointestinal (GI) microbiota but can also cause invasive infections, especially in immunocompromised hosts. Enterococci display intrinsic resistance to many antibiotics, and most clinical E. faecium isolates have acquired vancomycin resistance, leaving clinicians with a limited repertoire of effective antibiotics. As such, vancomycin-resistant E. faecium (VREfm) has become an increasingly difficult to treat nosocomial pathogen that is often associated with treatment failure and recurrent infections. We followed a patient with recurrent E. faecium bloodstream infections (BSIs) of increasing severity, which ultimately became unresponsive to antibiotic combination therapy over the course of 7 years. Whole-genome sequencing (WGS) showed that the patient was colonized with closely related E. faecium strains for at least 2 years and that invasive isolates likely emerged from a large E. faecium population in the patient's gastrointestinal (GI) tract. The addition of bacteriophage (phage) therapy to the patient's antimicrobial regimen was associated with several months of clinical improvement and reduced intestinal burden of VRE and E. faecium. In vitro analysis showed that antibiotic and phage combination therapy improved bacterial growth suppression compared to therapy with either alone. Eventual E. faecium BSI recurrence was not associated with the development of antibiotic or phage resistance in post-treatment isolates. However, an anti-phage-neutralizing antibody response occurred that coincided with an increased relative abundance of VRE in the GI tract, both of which may have contributed to clinical failure. Taken together, these findings highlight the potential utility and limitations of phage therapy to treat antibiotic-resistant enterococcal infections. IMPORTANCE: Phage therapy is an emerging therapeutic approach for treating bacterial infections that do not respond to traditional antibiotics. The addition of phage therapy to systemic antibiotics to treat a patient with recurrent E. faecium infections that were non-responsive to antibiotics alone resulted in fewer hospitalizations and improved the patient's quality of life. Combination phage and antibiotic therapy reduced E. faecium and VRE abundance in the patient's stool. Eventually, an anti-phage antibody response emerged that was able to neutralize phage activity, which may have limited clinical efficacy. This study demonstrates the potential of phages as an additional option in the antimicrobial toolbox for treating invasive enterococcal infections and highlights the need for further investigation to ensure phage therapy can be deployed for maximum clinical benefit.

Emerging issues on Staphylococcus aureus endocarditis and the role in therapy of daptomycin plus fosfomycin.

INTRODUCTION: Methicillin-resistant and -susceptible Staphylococcus aureus (MRSA/MSSA) infections are a major global health-care problem. Bacteremia with S. aureus exhibits high rates of morbidity and mortality and can cause complicated infections such as infective endocarditis (IE). The emerging resistance profile of S. aureus is worrisome, and several international agencies have appealed for new treatment approaches to be developed. AREAS COVERED: Daptomycin presents a rapid bactericidal effect against MRSA and has been considered at least as effective as vancomycin in treating MRSA bacteremia. However, therapy failure is often related to deep-seated infections, e.g. endocarditis, with high bacterial inocula and daptomycin regimens <10 mg/kg/day. Current antibiotic options for treating invasive S. aureus infections have limitations in monotherapy. Daptomycin in combination with other antibiotics, e.g. fosfomycin, may be effective in improving clinical outcomes in patients with MRSA IE. EXPERT OPINION: Exploring therapeutic combinations has shown fosfomycin to have a unique mechanism of action and to be the most effective option in preventing the onset of resistance to and optimizing the efficacy of daptomycin, suggesting the synergistic combination of fosfomycin with daptomycin is a useful alternative treatment option for MSSA or MRSA IE.

Efficacy and safety of intravenous fosfomycin for the treatment of carbapenem-resistant Klebsiella pneumoniae.

The aim of the study was to evaluate clinical and microbiological efficacy and safety of intravenous fosfomycin for the treatment of carbapenem-resistant K. pneumoniae infections. All adult inpatients receiving 48 h of intravenous fosfomycin, alone or combined with other antibiotics were included in the study. Overall favorable clinical response rate was 75.3% among 94 patients. Clinical response rates were 92.3%, 72.2% and 56.0% for urinary tract infections, bacteremia and pneumonia, respectively. Microbiological eradication was achieved in 55 of 86 patients. 30-day mortality was 33.0%. Adverse events were generally mild. Common adverse events were hypokalemia (37.2%) and hypernatremia (22.3%). Intravenous fosfomycin is an effective antibiotic option with a good safety profile for the treatment of carbapenem-resistant K. pneumoniae infections. The most favorable clinical and microbiological responses are obtained in urinary tract infections. The efficacy of the drug in more severe infections, such as pneumonia and bacteremia, is comparable to the literature.

Aminoglycoside-mimicking carbonized polymer dots for bacteremia treatment.

Bacteremia and associated bacterial sepsis are potentially fatal and occur when the host response to microbial invasion is impaired or compromised. This motivated us to develop carbonized polymer dots (CPDsMan/AA) from a mixture of mannose (Man) and positively charged amino acids [AAs; lysine, arginine (Arg), or histidine] through a one-step mild pyrolysis procedure, which effectively inhibited drug-resistant bacterial strains isolated from septic patients. The as-prepared CPDsMan/AA showed broad-spectrum antibacterial activity, including multidrug-resistant bacteria, even in human plasma. The minimal inhibitory concentration of CPDsMan/Arg is ca. 1.0 µg mL-1, which is comparable to or lower than those of other tested antibiotics (e.g., ampicillin, gentamicin, and vancomycin). In addition to directly disrupting bacterial membranes, the CPDsMan/Arg feature a structure similar to aminoglycoside antibiotics that could bind to 16S rRNA, thereby blocking bacterial protein synthesis. In vitro cytotoxic and hemolytic assays demonstrated the high biocompatibility of the CPDsMan/AA. In addition, in vivo studies on methicillin-resistant Staphylococcus aureus-infected mice treated with the CPDsMan/Arg showed a significant decrease in mortality-even better than that of antibiotics. Overall, the synthesis of the CPDsMan/AA is cost-efficient, straightforward, and effective for treating bacteremia. The polymeric features of the CPDsMan/Arg, including cationic charges and specific groups, can be recognized as a safe and broad-spectrum biocide to lessen our reliance on antibiotics to treat systemic bacterial infections in the future.

Single Center Clinical Analysis of Bloodstream Infection Pathogens in Children with Acute Leukemia / 中国实验血液学杂志

OBJECTIVE@#To investigate the clinical features, distribution of pathogenic bacteria, and drug resistance of bloodstream infection in children with acute leukemia.@*METHODS@#Clinical data of 93 blood culture-positive children with acute leukemia from January 2015 to December 2019 in Department of Pediatrics, The Second Hospital of Anhui Medical University were analyzed retrospectively.@*RESULTS@#In these 93 cases, 78 cases were in the period of neutrophil deficiency. There were 54 Gram-negative bacteria (G-) (58.1%) found through blood culture, and the top 4 strains were Escherichia coli (15.1%), Klebsiella pneumoniae (13.9%), Pseudomonas aeruginosa (6.5%), and Enterobacter cloacae (6.5%). There were 39 Gram-positive bacteria (G+) (41.9%) detected, and the top 4 strains were Staphylococcus epidermidis (10.8%), Streptococcus pneumoniae (6.5%), Staphylococcus hemolyticus (5.4%), and Staphylococcus human (5.4%). Among 74 strains of pathogenic bacteria from acute lymphoblastic leukemia (ALL) children, there were 29 strains of G+ bacteria (39.2%) and 45 strains of G- bacteria (60.8%). While in 19 strains from acute myeloblastic leukemia (AML) patients, G- bacteria accounted for 47.4% and G+ bacteria accounted for 52.6%. In 15 ALL children without neutropenia, G+ bacteria made up the majority of the strains (66.7%). In the 93 strains of pathogenic bacteria, 13 (13.9%) strains were multidrug-resistant. Among them, extended-spectrum β-lactamases accounted for 42.9%, carbapenemase-resistant enzyme Klebsiella pneumoniae 15.4%, and carbapenemase-resistant enzyme Enterobacter cloacae strains 33.3%, which were detected from G- bacteria. While, 13.3% of methicillin-resistant coagulase-negative Staphylococci accounted for 13.3% detected from G+ bacteria, but linezolid, vancomycin, teicoplanin Staphylococcus and Enterococcus resistant were not found. The average procalcitonin (PCT) value of G- bacteria infection was (11.02±20.282) ng/ml, while in G+ infection it was (1.81±4.911) ng/ml, the difference was statistically significant (P<0.05). The mean value of C-reactive protein (CRP) in G- infection was (76.33±69.946) mg/L, and that in G+ infection was (38.34±57.951) mg/L. The prognosis of active treatment was good, and only one case died of septic shock complicated with disseminated intravascular coagulation (DIC) and gastrointestinal bleeding caused by carbapenemase-resistant enzyme enterobacteriaceae.@*CONCLUSION@#G- is the major bacteria in acute leukemia children with bloodstream infection, but the distribution of ALL and AML strains is different. G- bacteria dominates in ALL, while G+ bacteria and G- bacteria are equally distributed in AML. Non-agranulocytosis accompanied by bloodstream infections is dominant by G+ bacteria. The mean value of PCT and CRP are significantly higher in G- bacteria infection than in G+ bacteria.

Systematic Evaluation of the Accelerate Pheno System for Susceptibility Testing of Gram-Negative Bacteria Isolated from Blood Cultures.

Bacteremia is a major cause of morbidity and mortality. Rapid identification of pathogens for early targeted antimicrobial therapy is crucial for detecting emergence of antibiotic resistance and improving outcomes. However, there are limited data regarding the analytical performance of a rapid identification (ID) and antimicrobial susceptibility testing (AST) method like Accelerate Pheno blood culture detection system compared with the conventional methods routinely used in microbiology laboratories. We undertook a systematic quality improvement (QI) study to compare AST results obtained with Accelerate Pheno system rapid ID/AST system with a standard reference method in a university hospital microbiology laboratory. This was a single center, retrospective (5/10/19 to 8/1/19) and prospective (8/1/19 to 1/31/20) study that evaluated all blood cultures growing Gram-negative rods (GNR). We compared AST results obtained using the reference disk diffusion (DD) susceptibility method with those obtained by the Accelerate Pheno system. We calculated the error rates and categorical agreement between the Accelerate Pheno system and DD for each organism and specific drug tested. We evaluated 355 blood cultures growing GNR, of which 284 met the inclusion criteria. We grouped all Enterobacterales (n = 263) for analysis (156 Escherichia coli, 60 Klebsiella spp., 20 Proteus mirabilis, 17 Enterobacter spp., and 10 Serratia marcescens). Twenty-one Pseudomonas aeruginosa isolates were analyzed separately. For Enterobacterales, categorical agreement (CA) was ≥90% for amikacin (AMK), aztreonam (ATM), cefepime (FEP), ceftriaxone (CRO), ertapenem (ETP), gentamicin (GEN), meropenem (MEM), and tobramycin (TOB); and very major error (VME) was <5% for ampicillin/sulbactam (SAM), GEN, MEM, TOB, CRO, and ceftazidime (CAZ). For ciprofloxacin (CIP), CA was 87% and VME was 8%. For P. aeruginosa, CA was ≥90% for AMK and TOB, and VME was ≥5% for AMK, CAZ, GEN, MEM, piperacillin-tazobactam (TZP), and TOB. Accelerate Pheno rapid ID/AST system for GNR isolated from blood culture (BCs) was reliable for some but not all agents in the panel. Based on the findings from this study, our laboratory reports Accelerate Pheno system AST results only for Enterobacterales, and we limit our reports to CRO, CAZ, TZP, CIP, ATM, and GEN. IMPORTANCE This was an 8-month retrospective and prospective study looking at the analytical performance of the Accelerate Pheno system on clinical isolates obtained from patients seen in our tertiary care hospital. Most of the published literature on the analytical performance of Accelerate Pheno System has been from clinical trials with limited data from clinical microbiology laboratories postimplementation of the system. Here we compare the AST results on 355 blood cultures growing Gram-negative bacteria in Accelerate Pheno system with the CLSI reference disk diffusion (DD) method. The findings from this study highlight the "real-world" performance of the Accelerate Pheno system for Gram-negative bacteria from blood cultures. We provide data to show the reliable susceptibility testing results of Enterobacterales for most of the commonly used antimicrobial agents and significant limitation for susceptibility testing results of Pseudomonas aeruginosa on the Accelerate Pheno system.

Rapid resistance development to three antistaphylococcal therapies in antibiotic-tolerant staphylococcus aureus bacteremia.

Understating how antibiotic tolerance impacts subsequent resistance development in the clinical setting is important to identifying effective therapeutic interventions and prevention measures. This study describes a patient case of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia which rapidly developed resistance to three primary MRSA therapies and identifies genetic and metabolic changes selected in vivo that are associated with rapid resistance evolution. Index blood cultures displayed susceptibility to all (non-beta-lactam) antibiotics with the exception of trimethoprim/ sulfamethoxazole. One month after initial presentation, during the same encounter, blood cultures were again positive for MRSA, now displaying intermediate resistance to vancomycin and ceftaroline and resistance to daptomycin. Two weeks later, blood cultures were positive for a third time, still intermediate resistant to vancomycin and ceftaroline and resistant to daptomycin. Mutations in mprF and vraT were common to all multidrug resistant isolates whereas mutations in tagH, agrB and saeR and secondary mprF mutation emerged sequentially and transiently resulting in distinct in vitro phenotypes. The baseline mutation rate of the patient isolates was unremarkable ruling out the hypermutator phenotype as a contributor to the rapid emergence of resistance. However, the index isolate demonstrated pronounced tolerance to the antibiotic daptomycin, a phenotype that facilitates the subsequent development of resistance during antibiotic exposure. This study exemplifies the capacity of antibiotic-tolerant pathogens to rapidly develop both stable and transient genetic and phenotypic changes, over the course of a single patient encounter.

Clinical and bacterial characteristics of Pseudomonas aeruginosa affecting the outcome of patients with bacteraemic pneumonia.

Few studies have assessed the clinical and bacterial characteristics of Pseudomonas aeruginosa (PA) bacteraemic pneumonia (BP) episodes. This study analysed all non-duplicate PA-BP episodes from a tertiary hospital in 2013-2017. Epidemiology, clinical data, antimicrobial therapy and outcomes were recorded. Whole-genome sequencing was performed on PA blood isolates. The impact on early and late overall mortality of host, antimicrobial treatment and pathogen factors was assessed by multivariate logistic regression analysis. Of 55 PA-BP episodes, 32 (58.2%) were caused by extensively drug-resistant (XDR) PA. ST175 (32.7%) and ST235 (25.5%) were the most frequent high-risk clones. ß-Lactamases/carbapenemases were detected in 29 isolates, including blaVIM-2 (27.2%) and blaGES type (25.5%) [blaGES-5 (20.0%), blaGES-1 (3.6%) and blaGES-20 (1.8%)]. The most prevalent O-antigen serotypes were O4 (34.5%) and O11 (30.9%). Overall, an extensive virulome was identified in all isolates. Early mortality (56.4%) was independently associated with severe neutropenia (aOR = 4.64, 95% CI 1.11-19.33; P = 0.035) and inappropriate empirical antimicrobial therapy (aOR = 5.71, 95% CI 1.41-22.98; P = 0.014). Additionally, late mortality (67.3%) was influenced by septic shock (aOR = 8.85, 95% CI 2.00-39.16; P = 0.004) and XDR phenotype (aOR = 5.46, 95% CI 1.25-23.85; P = 0.024). Moreover, specific genetic backgrounds [ST235, blaGES, gyrA (T83I), parC (S87L), exoU and O11 serotype] showed significant differences in patient outcomes. Our results confirm the high mortality associated with PA-BP. Besides relevant clinical characteristics and inappropriate empirical therapy, bacteria-specific genetics factors, such as XDR phenotype, adversely affect the outcome of PA-BP.

Influence of Antimicrobial Stewardship and Molecular Rapid Diagnostic Tests on Antimicrobial Prescribing for Extended-Spectrum Beta-Lactamase- and Carbapenemase-Producing Escherichia coli and Klebsiella pneumoniae in Bloodstream Infection.

The objective of this study was to evaluate whether the addition of the Verigene BC-GN molecular rapid diagnostic test to standard antimicrobial stewardship practices (mRDT + ASP) decreased the time to optimal and effective antimicrobial therapy for patients with extended-spectrum beta-lactamase (ESBL)- and carbapenemase-producing Escherichia coli and Klebsiella pneumoniae bloodstream infections (BSI) compared to conventional microbiological methods with ASP (CONV + ASP). This was a multicenter, retrospective cohort study evaluating the time to optimal antimicrobial therapy in 5 years of patients with E. coli or K. pneumoniae BSI determined to be ESBL- or carbapenemase-producing by mRDT and/or CONV. Of the 378 patients included (mRDT + ASP, n = 164; CONV + ASP, n = 214), 339 received optimal antimicrobial therapy (mRDT + ASP, n = 161; CONV + ASP, n = 178), and 360 (mRDT + ASP, n = 163; CONV + ASP, n = 197) received effective antimicrobial therapy. The mRDT + ASP demonstrated a statistically significant decrease in the time to optimal antimicrobial therapy (20.5 h [interquartile range (IQR), 17.0 to 42.2 h] versus 50.1 h [IQR, 27.6 to 77.9 h]; P < 0.001) and the time to effective antimicrobial therapy (15.9 h [IQR, 1.9 to 25.7 h] versus 28.0 h [IQR, 9.5 to 56.7 h]; P < 0.001) compared to CONV + ASP, respectively. IMPORTANCE Our study supports the additional benefit of molecular rapid diagnostic test in combination with timely antimicrobial stewardship program (ASP) intervention on shortening the time to both optimal and effective antimicrobial therapy in patients with ESBL- or carbapenemase-producing Escherichia coli and Klebsiella pneumoniae bloodstream infections, compared to conventional microbiological methods and ASP. Gram-negative infections are associated with significant morbidity and mortality, often resulting in life-threatening organ dysfunction. Both resistance phenotypes confer resistance to many of our first-line antimicrobial agents with carbapenemase-producing Enterobacterales requiring novel beta-lactam and beta-lactamase inhibitor combinations or other susceptible non-beta-lactam antibiotics for treatment. National resistance trends in a cohort of hospitalized patients at U.S. hospitals during our study period demonstrate the increasing incidence of both resistance phenotypes, reinforcing the generalizability and timeliness of such analysis.

Resistance patterns and clinical outcomes of Klebsiella pneumoniae and invasive Klebsiella variicola in trauma patients.

Recent reclassification of the Klebsiella genus to include Klebsiella variicola, and its association with bacteremia and mortality, has raised concerns. We examined Klebsiella spp. infections among battlefield trauma patients, including occurrence of invasive K. variicola disease. Klebsiella isolates collected from 51 wounded military personnel (2009-2014) through the Trauma Infectious Disease Outcomes Study were examined using polymerase chain reaction (PCR) and pulsed-field gel electrophoresis. K. variicola isolates were evaluated for hypermucoviscosity phenotype by the string test. Patients were severely injured, largely from blast injuries, and all received antibiotics prior to Klebsiella isolation. Multidrug-resistant Klebsiella isolates were identified in 23 (45%) patients; however, there were no significant differences when patients with and without multidrug-resistant Klebsiella were compared. A total of 237 isolates initially identified as K. pneumoniae were analyzed, with 141 clinical isolates associated with infections (remaining were colonizing isolates collected through surveillance groin swabs). Using PCR sequencing, 221 (93%) isolates were confirmed as K. pneumoniae, 10 (4%) were K. variicola, and 6 (3%) were K. quasipneumoniae. Five K. variicola isolates were associated with infections. Compared to K. pneumoniae, infecting K. variicola isolates were more likely to be from blood (4/5 versus 24/134, p = 0.04), and less likely to be multidrug-resistant (0/5 versus 99/134, p<0.01). No K. variicola isolates demonstrated the hypermucoviscosity phenotype. Although K. variicola isolates were frequently isolated from bloodstream infections, they were less likely to be multidrug-resistant. Further work is needed to facilitate diagnosis of K. variicola and clarify its clinical significance in larger prospective studies.

The potential impact of discrepancies between automated susceptibility platforms and other testing metho`dologies for cefazolin in the treatment of Enterobacterales bloodstream infections.

Revised breakpoints for cefazolin (CFZ) against Enterobacterales may be difficult to implement with current automated susceptibility testing platforms and could falsely report organisms as susceptible, leading to inappropriate treatment for bloodstream infections (BSI). This was a retrospective cohort of adult patients with Enterobacterales BSI reported CFZ susceptible per Vitek®2. The primary outcome was the percentage susceptible by minimum inhibitory concentration (MIC) Gradient Test Strips and disk diffusion. Secondary outcomes included clinical outcomes between CFZ and non-CFZ-treated patients. Among 195 isolates reported CFZ-susceptible per Vitek®2, 84 (43.1%) were CFZ susceptible by MIC Gradient Test Strips vs 119 (61%) by disk diffusion. No difference was noted in 30-day all-cause mortality, secondary complications, or 30-day readmissions. Treatment failure was less likely to occur with source control (adjusted OR 0.06) and infectious disease consult (adjusted OR 0.37). There was a large degree of discrepancy between automated testing and manual methods; the clinical impact of this discrepancy warrants further investigation.

Optimal Empiric Polymyxin B Treatment of Patients Infected with Gram-Negative Organisms Detected Using a Blood Antimicrobial Surveillance Network in China.

BACKGROUND: Few pharmacodynamics studies to date have evaluated the efficacy and safety of polymyxin B (PMB) in treating patients with bloodstream infections (BSIs) in China. METHODS: Patients with BSIs were identified using an antimicrobial surveillance network, and their pathogens were isolated. Patients were treated with a loading dose of PMB followed by either a weight-based or weight-independent maintenance dose. Monte Carlo simulation was utilized to calculate the probability of target attainment (PTA) and cumulative fraction of response (CFR) against Gram-negative organisms in patients with normal or decreased renal function. RESULTS: A total of 10,066 Gram-negative organisms, including 5500 Escherichia coli (Eco), 2519 Klebsiella pneumoniae (Kpn), 501 Acinetobacter baumannii (Aba), were isolated from patients with BSIs. Although these strains were highly resistant to carbapenem, they remained susceptible to PMB. Among patients with renal impairment (mean CrCL, 42 mL/min), a PMB 2.5 mg/kg loading dose followed by a maintenance dose of 60 mg q12h reached ≥90% PTA against isolates with an MIC of 2 mg/L, with a low risk of toxicity. Among patients with normal renal function (mean CrCL, 123 mL/min), all simulated regimens showed PTAs of 25-80%. A weight-based loading dose followed by either a weight-based or weight-independent maintenance dose showed a promising CFR, especially in patients with renal impairment, with CFRs ≥90% against carbapenem-resistant Eco, Kpn, and Aba. Simulated regimens showed a disappointing CFR (<80%) against carbapenem-resistant Pae in patients with normal renal function. Based on the optimal balance of efficacy and toxicity, a fixed maintenance dose of 60 mg q12h among patients with renal impairment yielded a CFR similar to regimens based on total body weight and was associated with a probability of toxicity (12.5%) significantly lower than that of simulations based on total body weight. Among patients with normal renal function, a weight-based maintenance dose of 1.25 mg/kg q12h achieved a higher CFR than a fixed maintenance dose, without significantly increasing toxicity. CONCLUSION: A 2.5 mg/kg loading dose of PMB is optimal, regardless of renal function. A fixed maintenance dose of 60 mg q12h is recommended for empirical treatment of patients with renal impairment infected with Eco, Kpn, and Aba, whereas a weight-based maintenance dose of 1.25 mg/kg is recommended for patients with normal renal function.

Exploring the possible targeting strategies of liposomes against methicillin-resistant Staphylococcus aureus (MRSA).

Multi antibiotic-resistant bacterial infections are on the rise due to the overuse of antibiotics. Methicillin-resistant Staphylococcus aureus (MRSA) is one of the pathogens listed under the category of serious threats where vancomycin remains the mainstay treatment despite the availability of various antibacterial agents. Recently, decreased susceptibility to vancomycin from clinical isolates of MRSA has been reported and has drawn worldwide attention as it is often difficult to overcome and leads to increased medical costs, mortality, and longer hospital stays. Development of antibiotic delivery systems is often necessary to improve bioavailability and biodistribution, in order to reduce antibiotic resistance and increase the lifespan of antibiotics. Liposome entrapment has been used as a method to allow higher drug dosing apart from reducing toxicity associated with drugs. The surface of the liposomes can also be designed and enhanced with drug-release properties, active targeting, and stealth effects to prevent recognition by the mononuclear phagocyte system, thus enhancing its circulation time. The present review aimed to highlight the possible targeting strategies of liposomes against MRSA bacteremia systemically while investigating the magnitude of this effect on the minimum inhibitory concentration level.

A Longitudinal Study of Adult Patients with Staphylococcus aureus Bacteremia over 11 Years in Korea.

BACKGROUND: The temporal changes in the Staphylococcus aureus genotypes causing S. aureus bacteremia (SAB) and the corresponding clinical changes over the last decade in South Korea are rarely investigated. METHODS: A longitudinal study of adult SAB patients was conducted in a large referral hospital in Seoul, South Korea. Adult monomicrobial SAB patients were enrolled between August 2008 and December 2018. Genotyping was performed by multilocus sequence typing (MLST) and staphylococcal protein A (spa) typing. Trends in changes were identified by linear regression analysis. RESULTS: Of 1782 adult SAB patients, the blood isolates of 1,778 (99.8%) and 1,634 (91.7%) were determined to be MLST and spa type, respectively. ST5 (-2.626%/year) and ST239 (-0.354%/year) decreased during the study period (P < 0.001 for both), but ST72 (2.009%/yr)-and ST8 (0.567%/yr) increased (P < 0.001 for both). The most common genotype was changed from ST5 in 2008 (44.9%) to ST72 in 2018 (36.3%). Panton-Valentine leukocidin-positive spa-t008-MRSA (USA300) was found in 28.6%. Central venous catheter (CVC)-related SAB (-2.440%/yr) and persistent SAB (-1.016%/yr) decreased, but mortality and recurrence rates were unchanged. CONCLUSION: Over the last decade, the hospital clones ST5 and ST239 have been replaced by community genotype ST72. This was associated with decreased CVC-related and persistent SAB. Increased USA300 was observed in community and hospital settings. Further research is required to identify the reasons for the ST72 epidemic and predict the impending epidemic of ST8 strains, including USA300.

Local audit of empiric antibiotic therapy in bacteremia: A retrospective cohort study.

BACKGROUND: It is unclear if a local audit would be useful in providing guidance on how to improve local practice of empiric antibiotic therapy. We performed an audit of antibiotic therapy in bacteremia to evaluate the proportion and risk factors for inadequate empiric antibiotic coverage. METHODS: This retrospective cohort study included patients with positive blood cultures across 3 hospitals in Hamilton, Ontario, Canada during October of 2019. Antibiotic therapy was considered empiric if it was administered within 24 hours after blood culture collection. Adequate coverage was defined as when the isolate from blood culture was tested to be susceptible to the empiric antibiotic. A multivariable logistic regression model was used to predict inadequate empiric coverage. Diagnostic accuracy of a clinical pathway based on patient risk factors was compared to clinician's decision in predicting which bacteria to empirically cover. RESULTS: Of 201 bacteremia cases, empiric coverage was inadequate in 56 (27.9%) cases. Risk factors for inadequate empiric coverage included unknown source at initiation of antibiotic therapy (adjusted odds ratio (aOR) of 2.76 95% CI 1.27-6.01, P = 0.010) and prior antibiotic therapy within 90 days (aOR of 2.46 95% CI 1.30-4.74, P = 0.006). A clinical pathway that considered community-associated infection as low risk for Pseudomonas was better at ruling out Pseudomonas bacteremia with a negative likelihood ratio of 0.17 (95% CI 0.03-1.10) compared to clinician's decision with negative likelihood ratio of 0.34 (95% CI 0.10-1.22). CONCLUSIONS: An audit of antibiotic therapy in bacteremia is feasible and may provide useful feedback on how to locally improve empiric antibiotic therapy.

Bloodstream Infections due to Carbapenem-Resistant Klebsiella pneumoniae: A Single-Center Retrospective Study on Risk Factors and Therapy Options.

We aimed to compare efficacy of different patterns of antibiotics and explore the risk factors related to mortality in patients with bloodstream infections (BSIs) due to carbapenem-resistant Klebsiella pneumoniae (CRKP). This study retrospectively included 89 patients with BSIs due to CRKP with complete data during the year of 2018 in the First Affiliated Hospital of Zhejiang University School of Medicine. Overall, the 28-day mortality was 47.2% (42/89). Multivariate analysis of Cox regression revealed that hematological malignancy (hazard ratio [HR] 5.698; 95% confidence interval [CI], 2.405-13.504; p < 0.001) and Pitt bacteremia score (HR per unit increase, 1.303; 95% CI, 1.109-1.532; p = 0.001) were identified as independent predictors for 28-day mortality. Among 70 patients with appropriate therapy, 35 received tigecycline (TGC)-based therapy, 20 received polymyxin B (PMB)-based therapy, 9 received ceftazidime/avibactam-based therapy, and 6 patients had other kinds of antibiotics, including ciprofloxacin, amikacin, and cotrimoxazole. By adjusting variables selected by crude analysis, it showed that receiving PMB-based therapy provided a survival benefit comparing with TGC-based therapy (HR, 0.068; 95% CI, 0.018-0.260; p < 0.001). Hematological malignancy and Pitt bacteremia score were independent risk factors of death in patients with BSIs due to CRKP and PMB-based therapy improved survival rate compared with TGC-based therapy.

Treatment of Bacteremia Caused by Enterobacter spp.: Should the Potential for AmpC Induction Dictate Therapy? A Retrospective Study.

Objective: Carbapenems are considered treatment of choice for bacteremia caused by potential AmpC-producing bacteria, including Enterobacter spp. We aimed to compare mortality following carbapenem vs. alternative antibiotics for the treatment of Enterobacter spp. bacteremia. Patients and Methods: We conducted a retrospective study in two centers in Israel. We included hospitalized patients with Enterobacter bacteremia treated with third-generation cephalosporins (3GC), piperacillin/tazobactam, quinolones, or carbapenem monotherapy as the main antibiotic in the first week of treatment, between 2010 and 2017. Cefepime was excluded due to nonavailability during study years. The primary outcome was 30-day all-cause mortality. Univariate and multivariate analyses were conducted, introducing the main antibiotic as an independent variable. Results: Two hundred seventy-seven consecutive patients were included in the analyses. Of these, 73 were treated with 3GC, 39 with piperacillin/tazobactam, 104 with quinolones, and 61 with carbapenems. All-cause 30-day mortality was 16% (45 patients). The type of antibiotics was not significantly associated with mortality on univariate or multivariate analyses. With carbapenems as reference, adjusted odds ratios (ORs) for mortality were 0.708, 95% confidence interval (CI) 0.231-2.176 with 3GC; OR 1.172, 95% CI 0.388-3.537 with piperacillin/tazobactam; and OR 0.586, 95% CI 0.229-1.4 with quinolones. The main antibiotic was not associated with repeated growth of Entrobacter spp. in blood cultures or other clinical specimens. Resistance development was observed with 3GC and piperacillin/tazobactam. Conclusions: Carbapenem treatment was not advantageous to alternative antibiotics, including 3GC, among patients with Enterobacter spp. bacteremia in an observational study.

Clinical impact of cefepime breakpoint in patients with carbapenem-resistant Klebsiella pneumoniae bacteraemia.

The application of cefepime breakpoint for carbapenem-resistant Klebsiella pneumoniae (CRKP) bacteraemia has not been explored. Adult cases of monomicrobial bloodstream infection (BSI) caused by cefepime-susceptible [minimum inhibitory concentration (MIC) ≤8 mg/L] K. pneumoniae isolates with carbapenem resistance between 2010 and 2015 were reviewed. Patients treated with cefepime were compared with those treated by other active agents using a propensity score-matched analysis to assess therapeutic effectiveness. The primary endpoint was 30-day crude mortality. A total of 114 patients experienced cefepime-susceptible CRKP bacteraemia and 40 (35.1%) died during hospitalisation. A total of 33 patients (28.9%) received cefepime therapy. Fifteen patients (13.2%) had BSI due to carbapenemase-producing isolates, and 86.7% (13/15) of carbapenemase-producing isolates were classified as cefepime susceptible dose-dependent (SDD). In the multivariate logistic regression analysis, 30-day mortality was independently associated with the presence of a critical illness [adjusted odds ratio (aOR) = 12.89, 95% confidence interval (CI) 3.88-42.83; P < 0.001], pneumonia (aOR = 5.97, 95% CI 1.65-21.76; P = 0.007) and rapidly fatal underlying disease (aOR = 6.43, 95% CI 1.30-31.09; P = 0.02). In contrast, cefepime-based therapy (aOR = 0.03, 95% CI 0.003-0.38; P = 0.006) and combination therapy (aOR = 0.09, 95% CI 0.02-0.36; P = 0.001) were protective against a fatal outcome. Based on current breakpoints for Enterobacterales, cefepime therapy was not associated with an unfavourable outcome for CRKP BSI with MIC-based dosing strategies. However, the susceptibility result of SDD to cefepime should alert clinicians for possible therapeutic failure.

Management and treatment of Aerococcus bacteremia and endocarditis.

OBJECTIVES: We describe our multicenter experience on diagnosis and management of Aerococcus bacteremia including the susceptibility profile of Aerococcus species and a suggested algorithm for clinicians. METHODS: Retrospective study of all patients with positive blood cultures for Aerococcus species from January 2005 to July 2020 in our institution with clinical data and susceptibility profile. Data were collected from both electronic health record and clinical microbiology laboratory database. RESULTS: There were 219 unique isolates with only the susceptibility profiles available, while 81 patients had clinical information available. Forty-nine of those cases were deemed as true bloodstream infection and the rest were of unclear clinical significance. Cases of endocarditis (n = 7) were high-grade, monomicrobial bacteremia caused by Aerococcus urinae. Patients with endocarditis were younger (66 vs 80 p < 0.05). The risk for endocarditis was higher if duration of symptoms was longer than 7 days (OR 105, 95% CI: 5-2271), or if there were septic emboli (OR 71, 95% CI: 3-1612). A DENOVA score cutoff of ≥ 3 was 100% sensitive and 89% specific in detecting endocarditis. The 30-day and 3-month all-cause mortality for bacteremia was 17% and 24%, respectively. Six out of seven patients with endocarditis survived. CONCLUSIONS: Antibiotic regimen for aerococcal bloodstream infections and endocarditis should be guided by species identification and antimicrobial susceptibility testing. DENOVA scoring system's performance in this study is more congruent to other studies. Hence, it can be used as an adjunctive tool in assessing the need for echocardiogram to rule out endocarditis. In our experience, two and four weeks of treatment for bloodstream infections and endocarditis, respectively, had good outcomes.

Clinical syndromes and treatment location predict utility of carbapenem sparing therapies in ceftriaxone-non-susceptible Escherichia coli bloodstream infection.

BACKGROUND: Cefiderocol, ceftazidime-avibactam, ceftolozane-tazobactam, intravenous fosfomycin and plazomicin represent potential carbapenem sparing agents for extended-spectrum-beta-lactamase or AmpC beta-lactamase producing Escherichia coli infection. However, available data is limited in predicting the volume of carbapenem therapy which could be substituted and real-world contraindications. METHODS: We determined the number of carbapenem days of therapy (DOT) which could be substituted and frequent contraindications accounting for antimicrobial susceptibility and site of infection in an unselected cohort with ceftriaxone-non-susceptible E. coli bacteremia at a single health network from 2015 to 2016. Individual patient data was used to calculate DOT and substitution for each agent. RESULTS: There were 108 episodes of E. coli bacteremia resulting in 67.2 carbapenem DOT/100 patient-days of antimicrobial therapy administered. Ceftazidime-avibactam could be used to substitute 36.2 DOT/100 patient-days (54%) for inpatient definitive therapy, ceftolozane-tazobactam for 34.7 DOT/100 patient-days (52%), cefiderocol for 27.1 DOT/100 patient-days (40%), fosfomycin for 23.3 DOT /100 patient-days (35%) and plazomicin for 27.1 DOT/100 patient-days (40%). Non-urinary tract source of infection was the most frequent contraindication to fosfomycin (25), plazomicin (26) and cefiderocol (26). Use in outpatient parenteral antimicrobial therapy (OPAT) programs accounted for 40% of DOT, all of which could be substituted if stability data allowed for ceftazidime-avibactam and ceftolozane-tazobactam. CONCLUSIONS: All tested agents could be used to replace a significant volume of carbapenem therapy. Establishing stability of these agents for use in OPAT is required for maximizing their use as carbapenem sparing agents while randomized clinical data is awaited for some of these agents in resistant E. coli bacteremia.