Breakthrough Bacteremia Research Articles

Transcatheter Aortic Valve Replacement–Associated Prosthetic Valve Endocarditis Due to Pseudomonas aeruginosa

Abstract Introduction In patients unsuitable for surgical aortic valve replacement (SAVR), transcatheter aortic valve replacement (TAVR) is an alternative treatment modality for severe aortic stenosis. Prosthetic valve endocarditis (PVE) is uncommon after TAVR, and TAVR-PVE due to Pseudomonas aeruginosa is rare. We report a patient with P. aeruginosa TAVR-PVE and review the literature on the topic. Case A 70-year-old woman with history of atrial fibrillation and severe aortic stenosis status post TAVR 4 months previously presented with a third episode of P. aeruginosa bacteremia. She initially developed P. aeruginosa bacteremia 18 days after TAVR. She failed two 6-week courses of intravenous cefepime treatment and then developed P. aeruginosa breakthrough bacteremia while on her third course of intravenous cefepime. Surgical intervention was declined by the patient. Two prior transesophageal echocardiograms (TEEs) were negative for vegetation, but after her breakthrough bacteremia, a repeat TEE showed a 1.5 × 0.8-cm vegetation on the aortic valve. Patient and family declined further therapy and transitioned to hospice and died 5 days later. Discussion This is the sixth reported case of P. aeruginosa TAVR-PVE. Enterococcus faecalis, coagulase-negative Staphylococcus and Staphylococcus aureus, and streptococci are the most common etiologic agents causing TAVR-PVE. Diagnosis is difficult, and TEE may be nondiagnostic. Of the 6 reported cases, the only 2 to survive underwent SAVR despite high Society of Thoracic Surgery risk calculator scores. Conclusion TAVR-PVE due to P. aeruginosa is rare and will likely not be cured by medical therapy alone. Surgical intervention with SAVR should be considered as the only available curative therapy despite high Society of Thoracic Surgery surgical risk scores.

Pseudomonas aeruginosa ventricular assist device infections: findings from ineffective phage therapies in five cases.

Left ventricular assist devices (LVAD) are increasingly used for management of heart failure; infection remains a frequent complication. Phage therapy has been successful in a variety of antibiotic refractory infections and is of interest in treating LVAD infections. We performed a retrospective review of four patients that underwent five separate courses of intravenous (IV) phage therapy with concomitant antibiotic for treatment of endovascular Pseudomonas aeruginosa LVAD infection. We assessed phage susceptibility, bacterial strain sequencing, serum neutralization, biofilm activity, and shelf-life of phage preparations. Five treatments of one to four wild-type virulent phage(s) were administered for 14-51 days after informed consent and regulatory approval. There was no successful outcome. Breakthrough bacteremia occurred in four of five treatments. Two patients died from the underlying infection. We noted a variable decline in phage susceptibility following three of five treatments, four of four tested developed serum neutralization, and prophage presence was confirmed in isolates of two tested patients. Two phage preparations showed an initial titer drop. Phage biofilm activity was confirmed in two. Phage susceptibility alone was not predictive of clinical efficacy in P. aeruginosa endovascular LVAD infection. IV phage was associated with serum neutralization in most cases though lack of clinical effect may be multifactorial including presence of multiple bacterial isolates with varying phage susceptibility, presence of prophages, decline in phage titers, and possible lack of biofilm activity. Breakthrough bacteremia occurred frequently (while the organism remained susceptible to administered phage) and is an important safety consideration.

Risk factors for resistant gram-positive bacteremia in febrile neutropenic patients with cancer

BackgroundGram-positive bacteria are frequently resistant to empirical beta‐lactams in febrile neutropenic patients with cancer. As microbiology and antibiotic susceptibility changes, we reevaluated the risk factors for resistant Gram-positive bacteremia in febrile neutropenic patients with cancer. MethodsEpisodes of bacteremic febrile neutropenia in Seoul National University Hospital from July 2019 to June 2022 were reviewed. Resistant Gram-positive bacteria were defined as a pathogen susceptible only to glycopeptide or linezolid in vitro (e.g., methicillin-resistant staphylococci, penicillin-resistant viridans streptococci, and ampicillin-resistant enterococci). Episodes were compared to identify independent risk factors for resistant Gram-positive bacteremia. ResultsOf 225 episodes, 78 (34.7%) involved resistant Gram-positive bacteremia. Multivariate analysis revealed that breakthrough bacteremia while being administered antibiotics (adjusted odds ratio [aOR], 6.794; 95% confidence interval [95% CI], 3.130–14.749; P < 0.001) and catheter-related infection (aOR 4.039, 95% CI 1.366–11.946; P = 0.012) were associated with resistant Gram-positive bacteremia. Chronic liver disease (aOR 0.231, 95% CI 0.059–0.905; P = 0.035) and hypotension at bacteremia (aOR 0.454, 95% CI 0.218–0.945; P = 0.035) were inversely associated with resistant Gram-positive bacteremia. ConclusionsResistant Gram-positive bacteria should be considered in breakthrough bacteremia and catheter-related infection in febrile neutropenic patients with cancer.

Leuconostoc lactis Bacteremia and Neutropenic Fever

Abstract The epidemiology of bacteremic infections in neutropenic patients has shifted from a previous majority involving gram-positive cocci to an increasing preponderance of gram-negative Enterobacteriaceae species and Pseudomonas aeruginosa. Recommended empiric antimicrobial treatment regimens include an antipseudomonal β-lactam or carbapenem agent while considering risk factors for the possibility of extended-spectrum β-lactamase– or carbapenemase-producing organisms. The addition of vancomycin is generally reserved for the chance of gram-positive cocci infection, principally in patients with central intravascular catheters or soft tissue infections. Persistent or breakthrough bacteremia despite receiving this glycopeptide drug should prompt the clinician to contemplate not only the possibility of vancomycin-resistant enterococci, but also other organisms that possess intrinsic resistance vancomycin, including Leuconostoc species.

Risk factors and outcomes associated with persistent vancomycin resistant Enterococcal Bacteremia

BackgroundPrior studies have identified that vancomycin resistant enterococcus (VRE) bacteremia that persists for four days or more is an independent predictor of mortality. Despite this, there is no published data to identify those patients at highest risk of developing persistent VRE bacteremia.MethodsThis was a single center, retrospective, case-control study of adult patients with a VRE bloodstream infection (BSI). Case patients were those with persistent bacteremia (≥ 4 days despite VRE-directed therapy) and control patients were those with non-persistent bacteremia. Logistic regression was used to assess risk factors associated with persistent VRE BSIs. Secondary outcomes included in-hospital mortality, recurrent bacteremia, and breakthrough bacteremia.ResultsDuring the study period, 24/108 (22%) patients had persistently positive blood cultures. Risk factors for persistent bacteremia included severe neutropenia (OR 2.13), 4 out of 4 positive index blood cultures (OR 11.29) and lack of source control (OR 11.88). In an unadjusted analysis, no statistically significant differences in in-hospital mortality (58% versus 40%; p = 0.121), recurrent bacteremia (17% versus 6%; p = 0.090), or breakthrough bacteremia (13% versus 7%; p = 0.402) were observed between groups.ConclusionPatients with severe neutropenia, 4 out of 4 positive index blood culture bottles, and lack of source control were more likely to develop persistent VRE bacteremia despite directed antibiotic treatment.

Bacteremia in Children with Solid Tumors: Etiology, Antimicrobial Susceptibility, Factors Associated with Multidrug Resistance, and Mortality.

This retrospective study aims to describe the etiology and resistance patterns of pathogens causing bacteremia in children with solid tumors in a tertiary pediatric hematology-oncology center in Jerusalem, Israel (2011-2019). Factors associated with multidrug-resistant (MDR) bacteremia and mortality were analyzed. A total of 228 pathogens were isolated in 126 patients; 61.0% were gram-negative rods (GNR) and 38.2% were gram-positive cocci (GPC). The most common pathogens were Klebsiella pneumoniae (19.3%), Escherichia coli (17.5%), and coagulase-negative staphylococci (16.2%). The proportion of MDR-GNR was 18.2%, while the proportion of MDR-GPC was 55.2%. In logistic regression analysis, breakthrough bacteremia on a penicillin-group antibiotic (odds ratio [OR] 5.69, [95% confidence interval 1.42-22.76], p-value = 0.014) was associated and underlying diagnosis of neuroblastoma was inversely associated (OR 0.17, [0.04-0.81], p-value = 0.026) with MDR-GNR bacteremia; while the previous hospitalizations' duration (OR 1.032/day, [1.01-1.06], p-value = 0.007) and oncologic treatment intensity (OR 2.19, [1.08-4.45, p-value = 0.03) were associated with MDR-GPC bacteremia. Shock, prolonged profound neutropenia, and pediatric intensive care unit (PICU) admission were associated with 7-day mortality; and relapsed disease, oncologic treatment intensity, prolonged profound neutropenia, and PICU admission-with 30-day mortality in the univariate analyses. Empirical antibiotic choice should be based on factors associated with MDR infections in this specific population.

Bacteremia in Hematopoietic Stem Cell Recipients Receiving Fluoroquinolone Prophylaxis: Incidence, Resistance, and Risk Factors.

BackgroundBacteremia is a common complication in hematopoietic stem cell transplant (HSCT) recipients. Prophylactic fluoroquinolone is recommended and used in these individuals. Breakthrough infections can occur with fluoroquinolone-resistant strains. We aimed to identify the incidence, resistance, and risk factors for bacteremia in HSCT recipients receiving fluoroquinolone prophylaxis.Materials and MethodsThis retrospective study was performed on patients who received fluoroquinolone prophylaxis and underwent autologous and allogeneic HSCT between 2015 and 2019. The incidence of bacteremia, comorbidity, treatment, and invasive procedures was compared in these patients with and without bacteremia.ResultsThere were 553 patients included in the study, 68 (12.3%) had bacteremia. The incidence of bacteremia is 8.2% of autologous HSCT recipients and 18.4% of allogeneic HSCT recipients. The significant risk factors associated with bacteremia were steroid-using (odds ratio [OR]:13.83, 95% confidence interval [CI]: 2.88 - 66.40), higher Charlson Comorbidity Index (CCI)-mean (OR: 1.57, 95% CI: 1.15 - 2.16), diabetes mellitus (OR: 4.29, 95% CI: 1.11 - 16.48) in autologous HSCT, steroid-using (OR: 6.84, 95% CI: 1.44 - 32.33), longer duration of neutropenia (OR: 1.05, 95% CI: 1.01 - 1.09) using central venous catheter (OR: 7.81, 95% CI: 1.00 - 61.23) in allogeneic HSCT. Seventy-three pathogens were isolated from a total of 68 bacteremia episodes. The most commonly occurring agents were Escherichia coli, Klebsiella pneumoniae and Enterococcus spp. Resistance to fluoroquinolones was 87.2%, 70.0% and 60.0% among these strains, respectively.ConclusionHigh CCI, diabetes mellitus, use of steroids and long-term neutropenia and use of central venous catheters were significantly associated with the breakthrough bacteremia in HSCT recipients receiving fluoroquinolone prophylaxis. Fluoroquinolone prophylaxis may reduce the incidence of bacteremia but may select strains resistant to fluoroquinolone.

574. De-escalation of Broad Spectrum Antibiotics during Cytokine Release Syndrome with Haploidentical Hematopoietic Stem Cell Transplantation

BackgroundFever is a common component of cytokine release syndrome (CRS) occurring in 90% of patients undergoing haploidentical hematopoietic stem cell transplantation (Haplo-HSCT). Fevers typically occur between the stem cell infusion (Day 0) and initiation of post-transplant cyclophosphamide and are often confused with febrile neutropenia (FN). Due to longer time to engraftment in Haplo-HSCT, CRS/FN exposes patients to prolonged courses of empiric broad spectrum antibiotic (BSA) therapy increasing the risk for multi-drug resistant organisms. Recently, at Yale New Haven Health, our practice has changed to now recommend antibiotic de-escalation to prophylaxis after 7 days of BSA if no infection is identified. The objective of this study was to assess the incidence of breakthrough infections with the de-escalation of BSA in CRS/FN. Secondary endpoints include rate of FN, rate of de-escalation, rate of recurrent fevers, duration of BSA, and positive blood culture data.MethodsThe patient population included those undergoing Haplo-HSCT between July 2016 and February 2020 and who developed CRS/FN between Day 0 and Day +5. Patients were excluded if they had prolonged hospitalization due to non-infectious complications or engraftment failure. Bacteremia was defined using NHSN definitions.ResultsOf the 53 Haplo-HSCTs assessed, 43 experienced CRS/FN. Thirty-five Haplo-HSCT (81%) with CRS/FN had negative cultures and 23 (66%) of these were de-escalated back to antibacterial prophylaxis. The median duration of BSA in the de-escalated group was 7 days (range 5–13) compared to 16.5 days range (13–21) in the non-de-escalated group (p< 0.001). Among those de-escalated, 7 (30%) had recurrent fever occurring at a median of 4 days (range 2–14) and were placed back on BSA. Two Haplo-HSCT (9%) that had fever after de-escalation developed a breakthrough bacteremia. No Haplo-HSCT after de-escalation had fever or re-admission for bacteremia 30 days after engraftment. Four Haplo-HSCT (9%) with CRS/FN had positive blood cultures; however, three (7%) were still able to be de-escalated from BSA to narrower agents based on susceptibilities.ConclusionDe-escalation of BSA in FN/CRS in Haplo-HSCT patients reduced unnecessary, prolonged antibiotic exposure with a low incidence of breakthrough infections.Disclosures All Authors: No reported disclosures

Antimicrobial escalation is not beneficial for Gram-negative bacteremia in adults who remained critically ill after appropriate empirical therapy

To study whether antimicrobial escalation is beneficial for the outcome of bacteremia patients receiving appropriate but less responsive antimicrobials as empirical therapy, adults with community-onset Gram-negative bacteremia and remained the critical illness after appropriate empirical therapy with third-generation cephalosporins were retrospective enrolled. Clinical outcomes included incidental nosocomial infections, breakthrough bacteremia, and in-hospital crude mortality were compared between patients receiving escalation and non-escalation therapy, after propensity-score (PS) matching at a ratio of 1:3 using independent predictors of 30-day mortality recognized by the multivariate regression model. Initially, the higher proportion of fatal comorbidities (McCabe classification) and 30-day mortality rates was exhibited in the escalation group (51 patients), compared to the non-escalation group (de-escalation, 81; non-switch, 95). After appropriate PS-matching, similar proportions of clinical variables between the escalation (45 patients) and no-escalation (135) groups, in terms of patient demographics, bacteremia severity at onset, severity and types of comorbidities, and bacteremia sources, were observed. Consequently, poorer clinical outcomes, such as the higher rate of incidental nosocomial infections and in-hospital crude mortality as well as the longer length of intravenous antimicrobial administration and hospitalization, were statistically evidenced in the escalation group, compared to the non-escalation group. Conclusively, for patients exhibiting poor responses to appropriate empirical therapy, antimicrobial escalation did not significantly result in improved outcomes; otherwise, clinicians should pay more attention to the strategy of supportive care or adequate control of septic complication.

In-Host Evolution of Daptomycin Resistance and Heteroresistance in Methicillin-Resistant Staphylococcus aureus Strains From Three Endocarditis Patients.

Daptomycin is considered an important alternative for the treatment of methicillin-resistant Staphylococcus aureus (MRSA). However, treatment failures associated with daptomycin nonsusceptibility isolates have been reported in recent years. In this study, we investigated serial MRSA strains from 3 endocarditis patients who had breakthrough bacteremia, despite treatment with daptomycin. The strains were analyzed by whole-genome sequencing, molecular typing, and mutation screening. Population analysis and growth curves were also applied to evaluate heteroresistance and fitness cost. This series of MRSA strains belonged to ST5, ST59, and ST4513. The daptomycin minimum inhibitory concentrations for these MRSA strains increased after daptomycin exposure, whereas daptomycin-resistant strains emerged with mutations in mprF and yycH. Population analysis profiling results demonstrated the presence of a daptomycin-heteroresistant subpopulation among daptomycin-susceptible MRSA strains, and no significant fitness cost was observed within these heteroresistant MRSA clones. We confirmed that daptomycin heteroresistance and resistance could emerge rapidly in MRSA strains of different lineages after daptomycin exposure. Further studies to fully understand the mechanism(s) underlying daptomycin resistance in MRSA are required.

Adjunctive therapy of intravenous colistin to intravenous tigecycline for adult patients with non-bacteremic post-surgical intra-abdominal infection due to carbapenem-resistant Acinetobacter baumannii

Post-surgical intra-abdominal infections (IAIs) due to carbapenem-resistant Acinetobacter baumannii (CRAB) are difficult to treat due to suboptimal peritoneal penetrations of several antimicrobial agents. Tigecycline has favorable outcomes of treating IAIs due to multidrug-resistant organisms but occurrence of breakthrough bacteremia has been observed because this agent has low serum level. Colistin has in vitro activity against CRAB but data on treatment of IAIs is limited due to poor peritoneal penetration. The purpose of this retrospective study is to explore the outcomes of adjunctive intravenous (IV) colistin to IV tigecycline in the treatment of IAIs caused by CRAB. Of 28 patients with non-bacteremic post-surgical IAIs due to CRAB, 14 patients received IV tigecycline alone and 14 patients received IV tigecycline with IV colistin. The 14-day, 30-day, in-hospital mortality rates, the rate of breakthrough bacteremia and the rate of bacterial eradication were not significantly different. The adjunctive therapy of IV colistin was associated with significantly higher rates of renal complications (10/14) than those receiving IV tigecycline alone (3/14) (P value = 0.023). In addition, the patients receiving adjunctive IV colistin had significantly more unfavorable non-clinical outcomes including longer length of hospital stay (P value = 0.049) and higher antimicrobial cost (P value = 0.008) and non-antimicrobial costs (P value = 0.037). In this study, adjunctive IV colistin to conventional IV tigecycline in the treatment of non-bacteremic post-surgical IAIs caused by CRAB did not yield clinical benefit but caused higher renal complication and unfavorable non-clinical outcomes.

In-host evolution of Staphylococcus epidermidis in a pacemaker-associated endocarditis resulting in increased antibiotic tolerance

Treatment failure in biofilm-associated bacterial infections is an important healthcare issue. In vitro studies and mouse models suggest that bacteria enter a slow-growing/non-growing state that results in transient tolerance to antibiotics in the absence of a specific resistance mechanism. However, little clinical confirmation of antibiotic tolerant bacteria in patients exists. In this study we investigate a Staphylococcus epidermidis pacemaker-associated endocarditis, in a patient who developed a break-through bacteremia despite taking antibiotics to which the S. epidermidis isolate is fully susceptible in vitro. Characterization of the clinical S. epidermidis isolates reveals in-host evolution over the 16-week infection period, resulting in increased antibiotic tolerance of the entire population due to a prolonged lag time until growth resumption and a reduced growth rate. Furthermore, we observe adaptation towards an increased biofilm formation capacity and genetic diversification of the S. epidermidis isolates within the patient.

A retrospective study (2001-2017) of acute and chronic morbidity and mortality associated with Staphylococcus aureus bacteraemia in a tertiary neonatal intensive care unit.

Staphylococcus aureus bacteraemia (SAB) in NICU patients can cause significant morbidity and mortality. To review early and late neonatal SAB with regard to risk factors, treatment, acute complications and long-term outcomes. A retrospective study of laboratory confirmed SAB over a 16-year period (November 2001-January 2017) in a tertiary neonatal unit in Ireland. A total of 74 neonates (MSSA n = 72, MRSA n = 2) were identified; 8.1% (n = 6) early sepsis, 91.8% (n = 68) late sepsis. Low birth weight neonates (born weighing less than 2500g) 80% (n = 59). Median age to bacteraemia 11days post-delivery (range = 0-100days); median onset early sepsis 1.5days versus late sepsis 12days. Complications of SAB; cellulitis n = 17, pneumonia n = 12, necrotising enterocolitis n = 7, thromobophlebitis n = 5, skin abscess formation n = 4, osteomyelitis n = 3, endocarditis n = 1. Late SAB mortality 6.4% (n = 3). Preterm and low birth weight infants were at highest risk of SAB. Only a small proportion of affected children had long-term clinical sequelae on follow-up. The high rate of recurrence and breakthrough bacteraemia suggests that early implementation of a targeted anti-staphylococcal antimicrobial regimen may be of particular benefit.

Fluoroquinolone Prophylaxis Selects for Meropenem-nonsusceptible Pseudomonas aeruginosa in Patients With Hematologic Malignancies and Hematopoietic Cell Transplant Recipients.

In Pseudomonas aeruginosa, fluoroquinolone exposure promotes resistance to carbapenems through upregulation of efflux pumps and transcriptional downregulation of the porin OprD. Evidence of this effect among hematologic malignancy (HM) patients or hematopoietic cell transplant (HCT) recipients receiving fluoroquinolone prophylaxis for neutropenia is lacking. We retrospectively evaluated episodes of P. aeruginosa bloodstream infections in HM patients or HCT recipients over a 7-year period at our institution. We determined the association of fluoroquinolone prophylaxis at the time of infection with meropenem susceptibility of P. aeruginosa breakthrough isolates and risk factors for meropenem nonsusceptibility. Whole-genome sequencing (WGS) and phenotypic assessments of meropenem efflux pump activity were performed on select isolates to determine the mechanisms of meropenem resistance. We analyzed 55 episodes of P. aeruginosa bacteremia among 51 patients. Breakthrough bacteremia while on fluoroquinolone prophylaxis was associated with nonsusceptibility to meropenem, but not to antipseudomonal β-lactams or aminoglycosides. The receipt of fluoroquinolone prophylaxis was independently predictive of bacteremia with a meropenem-nonsusceptible isolate. All meropenem-nonsusceptible isolates analyzed by WGS contained oprD inactivating mutations, and all meropenem-nonsusceptible isolates tested demonstrated reductions in the meropenem minimum inhibitory concentration in the presence of an efflux pump inhibitor. A phylogenetic analysis based on WGS revealed several clusters of closely related isolates from different patients. Fluoroquinolone prophylaxis in HM patients and HCT recipients is associated with breakthrough bacteremia with meropenem-nonsusceptible P. aeruginosa strains, likely due to both mutations increasing efflux pump activity and the epidemiology of P. aeruginosa bloodstream infections in our patient population.

Prevalence of vancomycin-variable Enterococcus faecium (VVE) among vanA-positive sterile site isolates and patient factors associated with VVE bacteremia.

Vancomycin-variable enterococci (VVE) are vanA-positive, vancomycin-susceptible enterococci with the ability to revert to a vancomycin-resistant phenotype on exposure to vancomycin. We sought to assess the prevalence of VVE and to determine clinical characteristics of patients infected with VVE. We prospectively collected Enterococcus faecium sterile site isolates from Toronto Invasive Bacterial Diseases Network hospitals from January 2015 to June 2016 and calculated VVE (defined as vanA-positive, vancomycin-susceptible isolates) prevalence among vanA-containing isolates. We performed chart reviews of VVE and vancomycin-resistant E. faecium (VRE) bacteremias identified from January 2012 to June 2016, and on a random sample of patients with bacteremia due to vanA/vanB-negative, vancomycin-susceptible enterococci (VSE) from January 2015 to June 2016. Clinical characteristics were compared and factors associated with mortality assessed. Because of the potential reversion from VVE to VRE, pulsed-field gel electrophoresis (PFGE) was performed for strains causing breakthrough bacteremia in order to identify relatedness among strains with different phenotypic resistance within the same patient. VVE comprised 47% (18/38) of vanA-positive isolates. The charts of 36 VRE, 25 VVE, and 79 VSE patients were reviewed. Central venous catheter associated bacteremia was more common in VVE (44%) and VRE patients (57%) than in VSE patients (28%) (P = 0.01). The Pitt bacteremia (OR 1.3, P = 0.002) and the Charlson score (OR 1.2, P = 0.008) were the only independent mortality predictors. PFGE of strains causing breakthrough bacteremia showed high within-patient clonality, irrespective of vanA-positivity or vancomycin-susceptibility. A substantial proportion of vanA-positive isolates are VVE and are therefore not detected with conventional selective culture methods. Bacteremia sources of patients with VVE are similar to those infected with VRE. We detected no association between VVE and 30-day mortality or breakthrough bacteremia.

Clinical predictors of Stenotrophomonas maltophilia bacteremia in adult patients with hematologic malignancy.

Stenotrophomonas maltophilia (SM) has emerged as an important nosocomial pathogen with high morbidity and mortality. Because of its unique antimicrobial susceptibility pattern, appropriate antimicrobial therapy for SM bacteremia is still challenging, especially in immunocompromised patients. The present study was performed to assess clinical predictors of SM bacteremia in adult patients with hematologic malignancy. From 2006 through 2016, a case-control study was performed at a tertiary-care hospital. Case patients were defined as SM bacteremia in patients with hematologic malignancy. Date- and location-matched controls were selected from among patients with gram-negative bacteremia (GNB) other than SM. A total of 118 cases of SM bacteremia were identified and compared to 118 controls. While pneumonia was the most common source of SM bacteremia, centralline-associated infection was most common in the controls. The overall 30-day mortality rate of cases with SM bacteremia was significantly higher than that of the controls (61.0 and 32.2%, respectively; P < 0.001). A multivariable analysis showed that polymicrobial infection, previous SM isolation, the number of antibiotics previously used ≥ 3, and breakthrough bacteremia during carbapenem therapy were significantly associated with SM bacteremia (all P < 0.01). Previous use of trimethoprim/sulfamethoxazole (TMP/SMX) was negatively association with SM bacteremia (P = 0.002). Our data suggest that SM is becoming a significant pathogen in patients with hematologic malignancy. Several clinical predictors of SM bacteremia can be used for appropriate antimicrobial therapy in hematologic patients with suspected GNB.

Evolution of Antibiotic Tolerance During Oxacillin, Daptomycin and Dalbavancin Therapy Results in Breakthrough Staphylococcus aureus Bacteremias

BackgroundClinicians can employ suppressive antimicrobial therapy in patients with persistent or relapsing bacteremia. However, bacteria with favorable susceptibility profiles may exhibit antimicrobial tolerance wherein bacteria cannot proliferate yet can survive in high concentrations of antibiotics. The antimicrobial tolerance phenotype can thwart efforts to prevent bacteremia recurrence with prolonged exposure to antimicrobials and may contribute to breakthrough bacteremias while the patient is receiving active therapy. Here we present a patient case consisting of multiple episodes of breakthrough Staphylococcus aureus bacteremia over several years in the setting of appropriately dosed antimicrobial suppressive therapy and describe organism mutations that developed during therapy.MethodsSix clinical bloodstream isolates were recovered from the patient during distinct episodes of MSSA bacteremia over a 5-year period. The identified source for each bacteremia was a central line infection (CLABSI). Isolates recovered were susceptible to the individual therapies received, which included oxacillin, daptomycin, and dalbavancin. Bacterial whole genome sequence data were collected using Illumina technology.ResultsThe first two isolates (USA600) and the last four isolates (USA800) represent distinct populations and suggest that a distinct MSSA strain displaced the previous population between bacteremia episodes 2 and 3. Of note, all of these strains were able to survive and establish breakthrough bacteremias despite favorable susceptibility profiles to the agents used as suppressive therapy. Although the MICs remain low and in the susceptible range to oxacillin, daptomycin, and dalbavancin, these isolates progressively developed significant antimicrobial tolerance phenotypes, which coincided with mutations in walK (yycG), htrA2, ftsW, ebh and iarS that may be advantageous to survival under antibiotic pressure.ConclusionThese genetic, phenotypic and patient case data identify important changes that can occur in bacterial populations over time that are distinct from antibiotic susceptibility. These findings point to factors that may result in breakthrough bacteremia, limiting the clinical utility of antimicrobial suppressive therapy.Disclosures W. Rose, Theravance: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Speaker honorarium; Merck: Grant Investigator, Research grant; The Medicines Company: Speaker’s Bureau, Speaker honorarium; Visante, Inc: Consultant, Consulting fee.

Multicenter Study of Clinical Features of Breakthrough Acinetobacter Bacteremia during Carbapenem Therapy.

Breakthrough Acinetobacter bacteremia during carbapenem therapy is not uncommon, and it creates therapeutic dilemmas for clinicians. This study was conducted to evaluate the clinical and microbiological characteristics of breakthrough Acinetobacter bacteremia during carbapenem therapy and to assess the efficacy of various antimicrobial therapies. We analyzed 100 adults who developed breakthrough Acinetobacter bacteremia during carbapenem therapy at 4 medical centers over a 6-year period. Their 30-day mortality rate was 57.0%, and the carbapenem resistance rate of their isolates was 87.0%. Among patients with carbapenem-resistant Acinetobacter bacteremia, breakthrough bacteremia during carbapenem therapy was associated with a significantly higher 14-day mortality (51.7% versus 37.4%, respectively; P = 0.025 by bivariate analysis) and a higher 30-day mortality (P = 0.037 by log rank test of survival analysis) than in the nonbreakthrough group. For the treatment of breakthrough Acinetobacter bacteremia during carbapenem therapy, tigecycline-based therapy was associated with a significantly higher 30-day mortality (80.0%) than those with continued carbapenem therapy (52.5%) and colistin-based therapy (57.9%) by survival analysis (P = 0.047 and 0.045 by log rank test, respectively). Cox regression controlling for confounders, including severity of illness indices, demonstrated that treatment with tigecycline-based therapy for breakthrough Acinetobacter bacteremia was an independent predictor of 30-day mortality (hazard ratio, 3.659; 95% confidence interval, 1.794 to 7.465; P < 0.001). Patients with breakthrough Acinetobacter bacteremia during carbapenem therapy posed a high mortality rate. Tigecycline should be used cautiously for the treatment of breakthrough Acinetobacter bacteremia that develops during carbapenem therapy.

Clinical characteristics and outcomes of Pseudomonas aeruginosa bacteremia in febrile neutropenic children and adolescents with the impact of antibiotic resistance: a retrospective study

BackgroundAlthough the proportion of Pseudomonas aeruginosa infections has reduced after the introduction of antibiotics with anti-pseudomonal effects, P. aeruginosa bacteremia still causes high mortality in immunocompromised patients. This study determined the clinical characteristics and outcomes of P. aeruginosa bacteremia and the antibiotic susceptibilities of strains isolated from febrile neutropenic patients.MethodsThirty-one febrile neutropenic children and adolescents with underlying hematologic/oncologic disorders diagnosed with P. aeruginosa bacteremia between 2011 and 2016 were enrolled in the study. Their medical records were retrospectively reviewed to evaluate the demographic and clinical characteristics. Antibiotic susceptibility rates of the isolated P. aeruginosa to eight antibiotic categories (anti-pseudomonal penicillin, anti-pseudomonal penicillin and β-lactamase inhibitor combination, anti-pseudomonal cephalosporin, monobactam, carbapenem, aminoglycoside, fluoroquinolone, and colistin) were also determined. Among the investigated factors, risk factors for mortality and infections by a multidrug-resistance (MDR) strain were determined.ResultsThirty-six episodes of P. aeruginosa bacteremia were identified. The mean age of the enrolled patients was 9.5 ± 5.4 years, and 26 (72.2%) episodes occurred in boys. Acute myeloid leukemia (41.7%) and acute lymphoblastic leukemia (33.3%) were the most common underlying disorders. The 30-day mortality was 38.9%, and 36.1% of the episodes were caused by MDR strains. The deceased patients were more likely to experience breakthrough infection (P = 0.036) and bacteremia (P = 0.005) due to MDR strains when compared with the patients who survived. The survived patients more likely received appropriate empirical antibiotic therapy (P = 0.024) and anti-pseudomonal β-lactam and aminoglycoside combination therapy (P = 0.039) compared with the deceased patients. The antibiotic susceptibility rates of the isolated P. aeruginosa strains were as follows: piperacillin/tazobactam, 67.6%; meropenem, 72.2%; and amikacin, 100%.ConclusionsMortality due to P. aeruginosa bacteremia remained at 38.9% in this study, and more than one-third of the isolated strains were MDR. In this context, empirical antibiotic combination therapy to expand the antibiotic spectrum may be a strategy to reduce mortality due to P. aeruginosa bacteremia in febrile neutropenic patients.

Bacteremia during neutropenic episodes in children undergoing hematopoietic stem cell transplantation with ciprofloxacin and penicillin prophylaxis.

Bacteremia during neutropenic episodes is a cause of morbidity and mortality in patients undergoing hematopoietic stem cell transplantation (HSCT). We have used oral ciprofloxacin and penicillin V, from the start of the conditioning regimen until engraftment, for the prophylaxis of bacterial infection. The objective of this study was to retrospectively analyze the prevalence of and risk factors for breakthrough bacteremia during neutropenic episodes in autologous and allogeneic HSCT patients. There were 215 patients enrolled, with a median age of 8.32years (range 0.51-21.64years) between 2002 and 2014. The common underlying diseases were thalassemia and acute leukemia. Bacteremia was documented in 33 patients (15.3%), with 39 microorganisms isolated. Escherichia coli (28.2%) and Streptococcus viridans (12.8%) were the most commonly isolated Gram-negative and Gram-positive bacteria, respectively. Multidrug resistant strains were found in 32 and 14.3% of Gram-negative and Gram-positive bacteria, respectively. Risk factors for bacteremia were receiving anti-thymocyte globulin (ATG) [odds ratio (OR) 2.44, 95% confidence interval (CI) 1.06-5.65, P=0.037] and umbilical cord blood as a stem cell graft (OR 6.60, 95% CI 1.04-41.83, P=0.045). In conclusion, the prevalence of bacteremia was 15.3% and the use of ATG and cord blood were risk factors for bacteremia during neutropenic episodes.