Joshua Wolf

Ethanol lock therapy in pediatric hematology and oncology

Central venous catheters are essential for treatment of cancer and hematologic disorders in children. Central line‐associated bloodstream infection (CLABSI) is the most common important complication and can lead to serious sequelae. Conventional antibiotic treatment is often unsuccessful. Ethanol lock therapy (ELT) has been shown to prevent CLABSI in various patient groups and might also be beneficial as adjunctive treatment for active infection. Efficacy and safety have not been adequately studied in the pediatric hematology/oncology population. Catheter occlusion and intraluminal clots have been reported. Routine use of ELT should not be recommended in this population until more data are available. Pediatr Blood Cancer 2013; 60: 18–25.

Genomic Analyses of Pneumococci from Children with Sickle Cell Disease Expose Host-Specific Bacterial Adaptations and Deficits in Current Interventions

Sickle cell disease (SCD) patients are at high risk of contracting pneumococcal infection. To address this risk, they receive pneumococcal vaccines, and antibiotic prophylaxis and treatment. To assess the impact of SCD and these interventions on pneumococcal genetic architecture, we examined the genomes of more than 300 pneumococcal isolates from SCD patients over 20 years. Modern SCD strains retained invasive capacity but shifted away from the serotypes used in vaccines. These strains had specific genetic changes related to antibiotic resistance, capsule biosynthesis, metabolism, and metal transport. A murine SCD model coupled with Tn-seq mutagenesis identified 60 noncapsular pneumococcal genes under differential selective pressure in SCD, which correlated with aspects of SCD pathophysiology. Further, virulence determinants in the SCD context were distinct from the general population, and protective capacity of potential antigens was lost over time in SCD. This highlights the importance of understanding bacterial pathogenesis in the context of high-risk individuals.

Central Line-associated Bloodstream Infection in Children: An Update on Treatment

www.pidj.com | 905 L central venous catheters (CVCs) are essential for modern pediatric practice. These devices terminate in a large central vein, usually the superior vena cava, and are used for administration of drugs, fluids and blood products; for blood collection and for hemodialysis. The most common, serious complication of CVC use is central line–associated bloodstream infection (CLABSI). Rates of CLABSI vary widely according to device type and patient population and can range from approximately 0.2 episodes per 1000 catheter-days in children with sickle cell disease to 11 per 1000 days in infants with intestinal insufficiency. The most common infecting organisms are coagulase-negative staphylococci (especially Staphylococcus epidermidis), Staphylococcus aureus, Enterococcus spp., Escherichia coli, Klebsiella spp., other enteric Gram-negative bacteria and Candida spp. Microorganisms are introduced predominantly through the hub during routine use or at the time of catheter insertion. After the first 14 days, intraluminal colonization is the most important source of infection. Important consequences of CLABSI include extended hospital stay (median of 12 days in 1 study), interruption of chemotherapy or other treatment, catheter removal (up to 50% of episodes), intravascular thrombosis, endocarditis, sepsis (up to 10%c) and rarely death. Techniques to prevent CVC colonization during insertion, such as maximum sterile barrier precautions, reduce the risk of CLABSI. After insertion, appropriate CVC dressings, careful catheter access technique, alcohol catheter caps and the use of prophylactic lock therapy with taurolidine, antibiotic or preservative-containing heparin solution can reduce the risk of infection in some groups. This review focuses on the management of CLABSI in children, outside the neonatal period, who have long-term tunneled CVCs (eg, Broviac or Hickman catheters, Bard Access Systems, Salt Lake City, Utah) or implantable ports (eg, Port-A-Cath, Smiths Medical, Dublin, Ohio). Major controversies include duration and choice of systemic antibiotic therapy, indications for catheter removal, screening for complications and the roles of adjunctive treatment and secondary prevention techniques. This review assesses the available literature and identifies pragmatic treatment strategies based on the best available evidence basis. The Infectious Diseases Society of America guidelines, which focus predominantly on adult patients, are referenced where a consensus recommendation is required but evidence is limited or conflicting. DIAGNOSIS AND DEFINITIONS The classic presentation of CLABSI is the development of fever and chills immediately after accessing a catheter that has been locked for some time. However, the range of clinical presentations is broad, and the catheter may not always be immediately considered as the source of fever. Most episodes are not associated with any visible abnormality at the site of the catheter. Unless an alternative source is identified, all bloodstream infections in patients with a CVC are classified as CLABSI. This surveillance definition may overestimate the true number of infections that are attributable to the CVC. Therefore, when there is evidence to confirm that the colonized device is the true source of infection, the more specific diagnosis of catheter-related bloodstream infection (CRBSI) is used (Fig. 1). Confirmatory tests include culture of the catheter tip, quantitative blood cultures or differential time to positivity (DTP) of blood cultures drawn from different sites. Data from pediatric oncology patients suggest that up to one third of CLABSI episodes are related to infections at other sites and are therefore not CRBSI. Definitive diagnosis of CRBSI can be important to identify those patients who might benefit from catheter removal or adjunctive therapy. CVC tip culture can identify CRBSI, but precludes salvage of the catheter. The most readily available technique to confirm CRBSI without catheter removal is the calculation of DTP between blood cultures drawn from the catheter and from a peripheral vein or separate lumen. In cases of true CRBSI, blood obtained through a colonized lumen will usually indicate growth ESPID REPORTS AnD REVIEwS

RelA Mutant Enterococcus faecium with Multiantibiotic Tolerance Arising in an Immunocompromised Host

ABSTRACT Serious bacterial infections in immunocompromised patients require highly effective antibacterial therapy for cure, and thus, this setting may reveal novel mechanisms by which bacteria circumvent antibiotics in the absence of immune pressure. Here, an infant with leukemia developed vancomycin-resistant Enterococcus faecium (VRE) bacteremia that persisted for 26 days despite appropriate antibiotic therapy. Sequencing of 22 consecutive VRE isolates identified the emergence of a single missense mutation (L152F) in relA, which constitutively activated the stringent response, resulting in elevated baseline levels of the alarmone guanosine tetraphosphate (ppGpp). Although the mutant remained susceptible to both linezolid and daptomycin in clinical MIC testing and during planktonic growth, it demonstrated tolerance to high doses of both antibiotics when growing in a biofilm. This biofilm-specific gain in resistance was reflected in the broad shift in transcript levels caused by the mutation. Only an experimental biofilm-targeting ClpP-activating antibiotic was able to kill the mutant strain in an established biofilm. The relA mutation was associated with a fitness trade-off, forming smaller and less-well-populated biofilms on biological surfaces. We conclude that clinically relevant relA mutations can emerge during prolonged VRE infection, causing baseline activation of the stringent response, subsequent antibiotic tolerance, and delayed eradication in an immunocompromised state. IMPORTANCE The increasing prevalence of antibiotic-resistant bacterial pathogens is a major challenge currently facing the medical community. Such pathogens are of particular importance in immunocompromised patients as these individuals may favor emergence of novel resistance determinants due to lack of innate immune defenses and intensive antibiotic exposure. During the course of chemotherapy, a patient developed prolonged bacteremia with vancomycin-resistant Enterococcus faecium that failed to clear despite multiple front-line antibiotics. The consecutive bloodstream isolates were sequenced, and a single missense mutation identified in the relA gene, the mediator of the stringent response. Strains harboring the mutation had elevated baseline levels of the alarmone and displayed heightened resistance to the bactericidal activity of multiple antibiotics, particularly in a biofilm. Using a new class of compounds that modulate ClpP activity, the biofilms were successfully eradicated. These data represent the first clinical emergence of mutations in the stringent response in vancomycin-resistant entereococci. The increasing prevalence of antibiotic-resistant bacterial pathogens is a major challenge currently facing the medical community. Such pathogens are of particular importance in immunocompromised patients as these individuals may favor emergence of novel resistance determinants due to lack of innate immune defenses and intensive antibiotic exposure. During the course of chemotherapy, a patient developed prolonged bacteremia with vancomycin-resistant Enterococcus faecium that failed to clear despite multiple front-line antibiotics. The consecutive bloodstream isolates were sequenced, and a single missense mutation identified in the relA gene, the mediator of the stringent response. Strains harboring the mutation had elevated baseline levels of the alarmone and displayed heightened resistance to the bactericidal activity of multiple antibiotics, particularly in a biofilm. Using a new class of compounds that modulate ClpP activity, the biofilms were successfully eradicated. These data represent the first clinical emergence of mutations in the stringent response in vancomycin-resistant entereococci.

Antimicrobial Stewardship Barriers and Goals in Pediatric Oncology and Bone Marrow Transplantation: A Survey of Antimicrobial Stewardship Practitioners.

We undertook a cross-sectional survey of antimicrobial stewardship clinicians in North America and Australasia regarding practices, goals, and barriers to implementation of stewardship for pediatric oncology patients. Goals and barriers were similar regardless of clinician or institutional characteristics and geographic location. Strategies addressing these factors could help optimize antimicrobial use.

Levofloxacin Prophylaxis During Induction Therapy for Pediatric Acute Lymphoblastic Leukemia

Background Infection is the most important cause of treatment-related morbidity and mortality in pediatric patients treated for acute lymphoblastic leukemia (ALL). Although routine in adults with leukemia, antibacterial prophylaxis is controversial in pediatrics because of insufficient evidence for its efficacy or antibiotic choice and concerns about promoting antibiotic resistance and Clostridium difficile infection. Methods This was a single-center, observational cohort study of patients with newly diagnosed ALL, comparing prospectively collected infection-related outcomes in patients who received no prophylaxis, levofloxacin prophylaxis, or other prophylaxis during induction therapy on the total XVI study. A propensity score-weighted logistic regression model was used to adjust for confounders. Results Of 344 included patients, 173 received no prophylaxis, 69 received levofloxacin prophylaxis, and 102 received other prophylaxis regimens. Patients receiving prophylaxis had longer duration of neutropenia. Prophylaxis reduced the odds of febrile neutropenia, likely bacterial infection, and bloodstream infection by ≥70%. Levofloxacin prophylaxis alone reduced these infections, but it also reduced cephalosporin, aminoglycoside, and vancomycin exposure and reduced the odds of C. difficile infection by >95%. No increase in breakthrough infections with antibiotic-resistant organisms was seen, but this cannot be excluded. Conclusions This is the largest study to date of antibacterial prophylaxis during induction therapy for pediatric ALL and the first to include a broad-spectrum fluoroquinolone. Prophylaxis prevented febrile neutropenia and systemic infection. Levofloxacin prophylaxis also minimized the use of treatment antibiotics and drastically reduced C. difficile infection. Although long-term antibiotic-resistance monitoring is needed, these data support using targeted prophylaxis with levofloxacin in children undergoing induction chemotherapy for ALL. Clinical Trials Registration NCT00549848.

No evidence of benefit from antibiotic lock therapy in pediatric oncology patients with central line‐related bloodstream infection: Results of a retrospective matched cohort study and review of the literature

Long‐term central venous catheters (CVCs) are essential to modern pediatric oncology practice, but central line‐related bloodstream infection (CRBSI) is a frequent and important complication. CVC salvage is often attempted but treatment failure is common due to persistent infection, delayed catheter removal, or subsequent relapse of infection, which can be associated with significant morbidity and cost. Adjunctive antibiotic lock therapy (ALT) has been proposed to reduce the risk of treatment failure, but insufficient data are available to confirm efficacy of this intervention.

Antibiotic susceptibility patterns of Staphylococcus aureus isolates from Australian children

Aim:  Staphylococcus aureus is an important cause of serious illness in children. Antibiotic resistance is an international problem and affects initial antibiotic choice. We aimed to describe susceptibility patterns of S. aureus isolates from Australian children to inform optimal empiric treatment of staphylococcal infections in this population.

Catheter-Related Complications in Children With Cancer Receiving Parenteral Nutrition: Change in Risk Is Moderated by Catheter Type.

Background: Although central venous catheters (CVCs) are essential to pediatric cancer care, complications are common (eg, occlusion, central line–associated bloodstream infection [CLABSI]). Parenteral nutrition (PN) and external CVCs are associated with an increased complication risk, but their interaction is unknown. Methods: A retrospective matched cohort study of pediatric oncology patients who received PN through subcutaneous ports or external CVCs. Complication rates were compared between CVC types during PN and non-PN periods (log-negative binomial model). Results: Risk of CLABSI was higher during PN for children with ports (relative risk [RR] = 39.6; 95% confidence interval, 5.0–309) or external CVCs (RR = 2.9; 95% confidence interval, 1.1–7.4). This increased risk during PN was greater for ports than for external CVCs (ratio of relative risks = 13.6). Occlusion risk was higher during PN in both groups (RR = 10.0 for ports; RR = 2.0 for external CVCs), and the increase was significantly greater in ports (ratio of relative risks, 4.9). Overall, complication rates for ports were much lower than for external CVCs during the non-PN period but similar during the PN period. Conclusion: Children with cancer who receive PN have increased risk of CLABSI and occlusion. The risk increase is greatest in children with ports: a 40- and 10-fold increase in infection risk and occlusion, respectively, resulting in similar complication rates during PN regardless of CVC type and negating the usual benefits of ports. Children with cancer who will require PN should have primary insertion of external CVCs where possible.

Antibiotic resistance threatens the efficacy of prophylaxis

The slow-motion catastrophe of antibiotic resistance has gained substantial attention as common bacterial infections become increasingly diffi cult to treat. In The Lancet Infectious Diseases, Aude Teillant and colleagues report an original approach to the issue. They used published data to model the eff ects of antibiotic resistance on antibacterial prophylaxis in patients under going surgery or cancer chemotherapy. Many researchers, clinicians, and media reports have focused on the poor treatment outcomes of antibioticresistant infections, supported by data showing that antibiotic-resistant infections are more diffi cult to cure and more likely to be fatal than are those that are susceptible to antibiotics. However, the eff ect of antibiotic resistance on the effi cacy of prophylactic regimens has been studied less thoroughly. Use of antibiotic prophylaxis is standard practice for many surgical procedures and some chemotherapy regimens because good evidence shows that it prevents infection and mortality. For example, for every 75 colorectal surgeries done, prophylaxis can prevent around 20 surgical site infections and one death. The effi cacy of prophylaxis is clearly aff ected by antibiotic resistance. Studies in men undergoing transrectal prostate biopsy show that pre-operative gut colonisation with resistant bacteria substantially reduces the effi cacy of antibacterial prophylaxis, leading to post-operative infection. Similarly, some studies of antibiotic prophylaxis in patients with cancer have shown a high rate of breakthrough infections with resistant organisms. Teillant and colleagues provide an important and novel perspective by estimating the possible eff ect of the waning effi cacy of prophylaxis on the risk of developing otherwise preventable infections. They conclude that a 30% reduction in the effi cacy of surgical and oncological prophylaxis would be disastrous, resulting in an additional 120 000 surgical site infections and 6300 infection-related deaths in the USA every year. Their study has some limitations: point estimates of surplus infections are provided without confi dence intervals, so the actual number of infections could diff er somewhat from the estimate. Furthermore, the authors assumed that estimates of prophylactic effi cacy in controlled trials translate directly to eff ectiveness in clinical practice, but research study populations diff er from the patient populations routinely treated in our hospitals so this assumption might be invalid. However, these limitations concern only the magnitude of the problem, not its overall importance. The inescapable conclusion is that the spread of antibiotic resistance will meaningfully increase the risk of infection in patients undergoing surgery and cancer chemotherapy, and that these infections will often be caused by bacteria that are diffi cult or impossible to treat. When this occurs, prophylaxis regimens might be changed in an attempt to keep surgical and cancer treatment safe. Indeed, interest is increasing in personalised antibiotic prophylaxis based on preoperative culture or rapid resistance tests. However, although modifi ed regimens might provide shortterm benefi ts, they will contribute to the problem of resistance in the long term. In patients with cancer, complete cessation of prophylaxis might be the only way to reduce the incidence of resistant infections as effi cacy wanes. Once the reality of routine failure of prophylaxis hits, it will be too late; we need to address the problem of antibiotic resistance now. However, the spectre of the “post-antimicrobial era” was raised long ago, and we already knew what to do then: develop new classes of antimicrobial drugs, reduce antibiotic exposure in animals and human beings, and prevent diseases through the use of vaccines and infection control. Despite this knowledge, most countries still have no coordinated strategy to reduce antimicrobial resistance, the new drug pipeline is drying up, and only a small amount of progress has been made towards reducing the use of antibiotics in livestock. The most direct action that clinicians can take is to improve antibiotic prescribing in human beings through support of antimicrobial stewardship. Anti microbial stewardship uses systemic interventions such as clinician education, guideline development, and form ulary restriction to optimise antibiotic use. How ever, attempts to improve prescribing have often been met with scepticism, manipulation, or even outright hostility. To improve stewardship outcomes, we need more research that focuses on understanding impediments to appropriate antibiotic prescribing, strategies that Lancet Infect Dis 2015