Activity of Cefiderocol and Comparators against Isolates from Cancer Patients.

Cefiderocol inhibited 97.5% of 478 Gram-negative isolates from cancer patients at ≤4 mg/liter. It had potent activity against extended-spectrum ß-lactamase-positive Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae (CRE), and nonfermenting Gram-negative bacilli, including Pseudomonas aeruginosa, Stenotrophomonas maltophilia, and Acinetobacter species isolates. Amikacin, ceftazidime-avibactam, and meropenem had appreciable activity against non-CRE Enterobacteriaceae No comparators were active against multidrug-resistant P. aeruginosa isolates. Only trimethoprim-sulfamethoxazole had appreciable activity against S. maltophilia isolates. Overall, cefiderocol was associated with the lowest level of resistance.

High Rates of Nonsusceptibility to Ceftazidime-avibactam and Identification of New Delhi Metallo-ß-lactamase Production in Enterobacteriaceae Bloodstream Infections at a Major Cancer Center.

Resistance to the novel ß-lactam/ß-lactamase inhibitor combination ceftazidime-avibactam (CAZ-AVI) among carbapenem-resistant Enterobacteriaceae (CRE) has infrequently been reported in the United States. We report unexpectedly high rates of resistance to CAZ-AVI in CRE bloodstream isolates at our institution associated with the nonoutbreak spread of New Delhi metallo-ß-lactamase in diverse Enterobacteriaceae species.

Ertapenem usage in cancer patients with and without neutropenia: a report on 97 cases from a comprehensive cancer center.

PURPOSE: Ertapenem is being increasingly utilized in cancer patients, but published data regarding its usage are limited. Our objective was to describe the various indications for ertapenem therapy and its safety and efficacy in cancer patients. METHODS: We conducted a retrospective cohort study of cancer patients who received monotherapy with ertapenem for at least 72 h, between January 2007 and February 2013. RESULTS: Among 97 unique patients who received ertapenem monotherapy, the most common indications were: (1) To facilitate discharge from the hospital of stable patients still requiring antimicrobial therapy (46 %). (2) Primary therapy of various documented infections (bacteremia, pneumonia, urinary tract infection, skin and skin structure infection) with ertapenem (28 %). (3) De-escalation from a different broad-spectrum agent or regimen to ertapenem within the hospital setting in patients not ready for discharge (25 %). The median age of the 97 patients studied was 59 years (range 9-87 years) with 52 % being men. Most patients had underlying hematologic malignancies (54 %), and 7 % were recipients of hematopoietic stem cell transplantation. Twenty-nine patients (30 %) were neutropenic, 26 % were diabetic, and 6 % had chronic lung disease. Primary ertapenem monotherapy was successful in all patients, de-escalation in 95.8 % of patients, and the strategy of discharge on outpatient therapy with ertapenem in 95.6 % of patients. Patients failing de-escalation or early discharge responded to alternative regimens. We documented no significant ertapenem associated toxicity or adverse events. CONCLUSIONS: Ertapenem appears to be safe and effective for several indications in cancer patients.

Understanding Middle East respiratory syndrome.

Middle East respiratory syndrome is an infection caused by a novel coronavirus. The primary source of the virus is infected camels in several countries in the Arabian peninsula. The infection is acquired by coming into contact with infected animals, animal products, or with patients who have the syndrome. Mortality for this syndrome is 30% to 40%, and treatment is supportive because no antiviral therapy exists.

Development and validation of a clinical model to predict the presence of ß-lactam resistance in viridans group streptococci causing bacteremia in neutropenic cancer patients.

BACKGROUND: Concern for serious infection due to ß-lactam-resistant viridans group streptococci (VGS) is a major factor driving empiric use of an anti-gram-positive antimicrobial in patients with febrile neutropenia. We sought to develop and validate a prediction model for the presence of ß-lactam resistance in VGS causing bloodstream infection (BSI) in neutropenic patients. METHODS: Data from 569 unique cases of VGS BSI in neutropenic patients from 2000 to 2010 at the MD Anderson Cancer Center were used to develop the clinical prediction model. Validation was done using 163 cases from 2011 to 2013. In vitro activity of ß-lactam agents was determined for 2011-2013 VGS bloodstream isolates. RESULTS: In vitro resistance to ß-lactam agents commonly used in the empiric treatment of febrile neutropenia was observed only for VGS isolates with a penicillin minimum inhibitory concentration (MIC) of ≥ 2 µg/mL. One hundred twenty-nine of 732 patients (17%) were infected with VGS strains with a penicillin MIC ≥ 2 µg/mL. For the derivation and validation cohorts, 98% of patients infected by VGS with a penicillin MIC of ≥ 2 µg/mL had at least 1 of the following risk factors: current use of a ß-lactam as antimicrobial prophylaxis, receipt of a ß-lactam antimicrobial in the previous 30 days, or nosocomial VGS BSI onset. Limiting empiric anti-gram-positive therapy to neutropenic patients having at least 1 of these 3 risk factors would have reduced such use by 42%. CONCLUSIONS: Simple clinical criteria can assist with targeting of anti-gram-positive therapy to febrile neutropenic patients at risk of serious ß-lactam-resistant VGS infection.

Neutropenic fever and sepsis: evaluation and management.

Neutropenia remains the predominant predisposing factor for infection in most cancer patients. Bacterial and fungal infections are common in this setting. Not all neutropenic patients have the same risk of developing severe infection or serious medical complications. Although all patients with neutropenia and fever should receive prompt, empiric antibiotic therapy, low-risk patients can be effectively managed without hospitalization-often with the administration of oral antibiotics. Other patients need hospital-based therapy. The emergence of resistant microorganisms has become a significant problem in neutropenic patients. Frequent epidemiologic surveys to detect the emergence of resistant organisms are recommended. Antibiotic stewardship and Infection Control Programs are important tools in combating resistant organisms.

The current spectrum of infection in cancer patients with chemotherapy related neutropenia.

Despite advancements in the treatment and supportive care of patients with malignant disorders, neutropenia remains the major side effect of most antineoplastic regimens. Infections occur frequently in neutropenic patients and are associated with considerable morbidity and mortality. The spectrum of infection continues to change, and is influenced by various factors including local epidemiology, the use of chemoprophylaxis, and the use of central venous catheters and other medical devices. Bacterial infections are common in the early stages of neutropenia, with fungal infections emerging if neutropenia persists beyond 7-10 days. Gram-positive organisms cause most bacteremic infections (although this trend appears to be changing), whereas infections at other sites are often caused by Gram-negative bacilli or are polymicrobial, especially if deep tissue infection is present. Candida spp., and Aspergillus spp., remain the most common fungal pathogens, although several opportunistic fungi have emerged. Resistance to antimicrobial and antifungal agents commonly used for the prevention and treatment of infections in neutropenic patients has become a significant problem. The prompt administration of appropriate, empiric, antimicrobial therapy, prior to the availability of microbiological culture results, is the standard of care. Up to date knowledge of the spectrum of infection and local susceptibility/resistance patterns, is critical. In this report, we describe the current spectrum of infection in patients with malignancies and neutropenia, and emphasize the fact that local and geographic differences are not infrequent. We recommend that individual institutions conduct periodic epidemiological surveys in order to have the latest data available for the optimal management of their patients.

Daptomycin use in neutropenic patients with documented gram-positive infections.

PURPOSE: The goal of this study was to describe the outcomes associated with daptomycin treatment of documented gram-positive infections in patients with neutropenia. METHODS: All patients with neutropenia (≤500 cells/m(3)) and at least one documented gram-positive culture from 2006-2009 were identified from a retrospective, multicenter, and observational registry (Cubicin(®) Outcome Registry and Experience (CORE(®))). Investigators assessed patient outcome (cured, improved, failed, nonevaluable) at the end of daptomycin therapy. All patients were included in the safety analysis. RESULTS: The efficacy population had 186 patients; 159 (85 %) patients had either cure (n = 108, 58 %) or improved (n = 51, 27 %) as an outcome. Success rates (cure plus improved) by the lowest WBC during daptomycin were 98/116 (84 %) for ≤100 cells/m(3) and 61/70 (87 %) for 101-499 cells/m(3), P = 0.6. Most patients had cancer; 135/186 (73 %) had hematological malignancy; 26/186 (14 %) had solid tumors, and 9 (5 %) had both. One hundred fifty-six (84 %) patients received other antibiotics before daptomycin treatment; 82 % vancomycin, of which 31 % failed vancomycin. The most common infections were bacteremia (78 %), skin and skin structure infections (8 %), and urinary tract infections/pyelonephritis (6 %). The most common pathogens were vancomycin-resistant Enterococcus faecium (47 %), methicillin-resistant Staphylococcus aureus (20 %), and coagulase-negative staphylococci (19 %). The median (min, max) initial daptomycin dose was 6 mg/kg (3.6, 8.3). The median (min, max) daptomycin duration of therapy was 14 days (1, 86). Possibly related adverse events occurred in 12/209 patients (6 %), and 13 patients (6 %) discontinued daptomycin due to adverse event. CONCLUSIONS: The results suggest that daptomycin appeared useful and well tolerated in neutropenic patients, and the degree of neutropenia did not affect daptomycin success rates. Comparative clinical trials are needed to confirm these findings.

Neutropenic enterocolitis, a growing concern in the era of widespread use of aggressive chemotherapy.

Neutropenic enterocolitis (NEC) is a life-threatening disease with substantial morbidity and mortality, seen primarily in patients with hematologic malignancies. The frequency of NEC has increased with the widespread use of chemotherapeutic agents such as the taxanes, which cause severe gastrointestinal mucositis. Neutropenic patients with fever and abdominal symptoms (cramping, pain, distention, diarrhea, GI bleeding), should undergo evaluation of the abdomen for bowel wall thickening of >4 mm, the hallmark of NEC. Clostridium difficile infection should be ruled out, as well as other etiologies such as graft-versus-host disease. Complications include bacteremia, which is often polymicrobial, hemorrhage, and bowel wall perforation/abscess formation. Management includes bowel rest, correction of cytopathies and coagulopathies, and broad spectrum antibiotics and antifungal agents. Surgical intervention may be necessary to manage complications such as hemorrhage and perforation and should be delayed, if possible, until recovery from neutropenia.

Carbapenem-resistant Acinetobacter baumannii: Colonization, Infection and Current Treatment Options.

Carbapenem-resistant Acinetobacter baumannii (CRAB) causes colonization and infection predominantly in hospitalized patients. Distinction between the two is a challenge. When CRAB is isolated from a non-sterile site (soft tissue, respiratory samples, etc.), it probably represents colonization unless clear signs of infection (fever, elevated white blood count, elevated inflammatory markers and abnormal imaging) are present. Treatment is warranted only for true infections. In normally sterile sites (blood, cerebrospinal fluid) the presence of indwelling medical devices (catheters, stents) should be considered when evaluating positive cultures. In the absence of such devices, the isolate represents an infection and should be treated. If an indwelling device is present and there are no signs of active infection, the device should be replaced if possible, and no treatment is required. If there are signs of an active infection the device should be removed or replaced, and treatment should be administered. Current treatments options and clinical data are limited. No agent or combination regimen has been shown to be superior to any other in randomized clinical trials. Ampicillin-sulbactam appears to have the best evidence for initial use. This is probably due to its ability to saturate penicillin-binding proteins 1 and 3 when given in high dose. Tigecycline when used should be given in high dose as well. Polymyxins are a treatment option but are difficult to dose correctly and have significant side effects. Newer treatment options such as eravacycline and cefiderocol have potential; however, currently there are not enough data to support their use as single agents. Combination therapy appears to be the best treatment option and should always include high-dose ampicillin-sulbactam combined with another active agent such as high-dose tigecycline, polymyxins, etc. These infections require a high complexity of skill, and an infectious disease specialist should be involved in the management of these patients.

In vitro activity of imipenem/releactam and comparator agents against clinical bacterial isolates from patients with cancer.

OBJECTIVES: Gram-negative bacilli (GNB) are currently the predominant bacterial pathogens in patients with cancer. Many GNB have become problematic due to the widespread emergence of resistance. Imipenem/relebactam (IMI/REL) is a combination of the carbapenem imipenem with relebactam, a non-ß-lactam ß-lactamase inhibitor. It is active against most pathogenic GNB including many that are resistant to other agents. We compared its in vitro activity to six other agents against 490 GNB recovered exclusively from patients with cancer because such data are scarce. METHODS: Clinical and Laboratory Standards Institute (CLSI) microbroth dilution methods were used for susceptibility testing. Whole genome sequencing (Illumina MiSeq) was performed on 30 selected isolates. RESULTS: IMI/REL was active against 98% of Enterobacterales and 87% of non-Enterobacterales isolates (excluding Stenotrophomonas maltophilia). It had potent activity against extended spectrum ß-lactamase-producing Escherichia coli, Klebsiella pneumoniae, and other Enterobacterales (Enterobacter cloacae, Citrobacter Spp., and Serratia Spp.) and moderate activity against carbapenem-resistant Enterobacterales. IMI/REL had potent activity against Achromobacter Spp., non-multidrug resistant Pseudomonas aeruginosa, and Sphingomonas paucimobilis and moderate activity against multidrug resistant P. aeruginosa. Overall, IMI/REL was associated with the lowest number of nonsusceptible isolates compared with six other agents (imipenem, meropenem, cefepime, piperacillin/tazobactam, amikacin, and tigecycline) commonly used in patients with cancer. Whole genome sequencing performed on 30 resistant isolates (10 each of E. coli, K. pneumonia, and P. aeruginosa) did not reveal any predominant mechanism of resistance to IMI/REL. CONCLUSION: Its in vitro activity indicates that IMI/REL might have a role to play in the treatment of Gram-negative infections in patients with cancer.

Current microbiology of percutaneous endoscopic gastrostomy tube (PEG tube) insertion site infections in patients with cancer.

PURPOSE: Percutaneous endoscopic gastrostomy (PEG) is frequently used to provide enteral access in cancer patients who are unable to swallow. Infection is an important complication in this setting. Current microbiological data are needed to guide infection prevention and treatment strategies. METHODS: The microbiological records of our institution (a 550-bed comprehensive cancer center) were retrospectively reviewed over an 8-month study period in order to identify patients who developed PEG tube insertion site infections, and review their microbiological details and susceptibility/resistance data. RESULTS: Fifty-eight episodes of PEG tube insertion site infections were identified. Of these, 31 (53%) were monomicrobial, and the rest were polymicrobial. The most common organisms isolated were Candida species, Staphylococcus aureus, and Pseudomonas aeruginosa. All infections were local (cellulitis, complicated skin, and skin structure infections including abdominal wall abscess) with no cases of concomitant bacteremia being documented. Most of the organisms isolated were susceptible to commonly used antimicrobial agents, although some quinolone-resistant and some multidrug-resistant organisms were isolated. CONCLUSIONS: This retrospective study provides descriptive data regarding PEG tube insertion site infections. These data have helped us update institutional guidelines for infection prevention and treatment as part of our focus on antimicrobial stewardship.

Emergence of linezolid-resistant coagulase-negative Staphylococcus in a cancer centre linked to increased linezolid utilization.

OBJECTIVES: The prevalence of linezolid-resistant coagulase-negative Staphylococcus (CoNS) in the MD Anderson Cancer Center rose from 0.6% in 2007 to 5.5% in 2009. The aim of our study was to analyse the relationship between linezolid use and an outbreak of linezolid-resistant CoNS. PATIENTS AND METHODS: We retrospectively identified 27 infection or colonization events. Eleven isolates were available for supplemental investigation; species identification, clonal relatedness and linezolid resistance mutation analysis. The medical records of the affected patients were reviewed and linezolid utilization data were obtained from the pharmacy. RESULTS: Available isolates were confirmed as clonally related Staphylococcus epidermidis. Partial 23S rRNA gene sequencing found a G2576T mutation in all of the isolates tested. All patients received linezolid within 3 months prior to an event. Patients without a prior hospitalization had a longer time from admission to event; 29 versus 3.5 days (P = 0.002). The outbreak was preceded by a 51% increase in inpatient linezolid utilization and 64% of affected patients belonged to the leukaemia service, which had a utilization rate 3.1 times that of the other services (95% confidence interval: 2.96-3.23). CONCLUSIONS: Increased linezolid utilization preceded the appearance of a linezolid-resistant CoNS clone. Patients probably acquired the clonal strain nosocomially, given the longer time from admission to event among patients with no previous admission to the MD Anderson Cancer Center. Linezolid administration then selected this strain, since all patients received linezolid prior to an event. A linezolid utilization rate of >or=13 defined daily doses/100 patient-days was similar to that reported in two other outbreaks and may be the threshold required to generate an outbreak.

Oral moxifloxacin for outpatient treatment of low-risk, febrile neutropenic patients.

OBJECTIVES: Low-risk febrile neutropenic patients can be treated without hospitalization with oral antibiotic regimens. Combination regimens are recommended. Our objective was to evaluate the feasibility of quinolone monotherapy (moxifloxacin) in this setting. METHODS: In this open-label pilot study, eligible low-risk febrile neutropenic patients identified using pre-defined criteria (MASCC Risk Index) received oral moxifloxacin (400 mg) in our emergency center and were discharged after a 4-8 h observation period to ensure clinical stability. They subsequently received moxifloxacin 400 mg daily as outpatients. Success of monotherapy, outpatient management, the development of adverse events, and major medical complications were recorded. RESULTS: The trial was closed without reaching the target sample size of 40 patients due to slow accrual. Twenty-one evaluable patients were enrolled, with sarcoma and breast cancer being the predominant underlying neoplasms. Most patients (76%) were severely neutropenic (

Daptomycin use in patients with cancer and neutropenia: data from a retrospective registry.

Clinical data for daptomycin in the treatment of neutropenic cancer patients with documented gram-positive infections are limited. For this study, neutropenic patients were identified from an ongoing retrospective registry (Cubicin Outcome Registry and Experience [CORE]; 2006 program year). Clinical outcomes included cure, improved, failed, and nonevaluable response, and were assessed at the end of daptomycin therapy. Patients who had a nonevaluable clinical response were only included in the safety analysis. Eighty-four patients were identified, of which 72 (86%) were clinically evaluable. Thirty-four (47%) evaluable patients had severe neutropenia (less than 100 cells/mm(3)). Hematologic malignancies were most common (82%). Bacteremia was the most common infection (76%), and vancomycin-resistant enterococci (50%), coagulase-negative staphylococci (24%), and Staphylococcus aureus (11%) were the most common pathogens isolated. Sixty-three patients (88%) received prior antibiotics, including vancomycin (83%), cefepime (17%), and linezolid (16%). The overall success rate (cure + improved) was 90%. Success rates stratified by degree of neutropenia were 85% for patients with less than 100 cells/mm(3), 93% for those with 100-499 cells/mm(3), and 100% for those with 500-1,000 cells/mm(3). The median final daptomycin dose was 6 mg/kg (range, 3-8) and the median duration of therapy was 13 days (range, 1-86). Of the 84 patients analyzed for safety, 24 (29%) developed 44 adverse events; only 5 (6%) patients had adverse events possibly related to daptomycin. The results suggest that daptomycin may be useful for specific cases involving neutropenic patients, and comparative clinical trials are feasible.

Administering an additional hepatitis B vaccination dose after 18 years maintains adequate long-term protection levels in healthcare workers.

Background: HBV (hepatitis B virus) vaccination in first year of life is recommended to prevent infection. Observational studies have suggested that vaccination at birth provides protection for 90% of the population for 30 years. Data on response to booster doses and long-term protection are lacking.Methods: We compared HBV antibody levels of healthcare students who were immunized for HBV with a primary series during their first year of life (primary) to students who were immunized with a primary series and received an additional dose at age 18 (boosted) four years earlier. Antibody titres ≥10 mIU/mL were considered adequate. Those that were inadequate received another dose and were reassessed.Results: We assessed 381 students, 80.1% were primary and 19.9% boosted. A significantly higher percentage of students in the boosted group had antibody titre levels ≥10 mIU/mL compared to primary group (88.1% vs. 41.3%, p < .001). Of 179 students in the primary group with inadequate antibody levels, 134 received a booster dose and 126 of them (94%) developed anti-HBs levels ≥10 mIU/mL. Of 9 students with inadequate levels in the boosted group, 8 received another booster dose and all developed adequate levels.Conclusions: Primary vaccination against HBV at birth does not necessarily provide lifelong adequate antibody levels. Boosting at 18 years reinforces antibody levels for at least four more years. Current guidelines recommend testing and boosting all medical personal. Based on our study, it may be prudent to extend this practice to all individuals who are at higher risk.

New antimicrobial agents for the treatment of bacterial infections in cancer patients.

Patients with cancer develop serious bacterial infections often, especially during periods of severe and prolonged neutropenia. Antibiotic usage for the prevention and treatment of bacterial infections in these high-risk patients leads to selection pressures resulting in the emergence and spread of resistant organisms. Many organisms acquire several resistance mechanisms, making them multi-drug-resistant (MDR) (defined as resistance to three or more different classes of antibiotics). These infections are associated with increased morbidity, mortality and costs. The development of novel antimicrobial agents with activity against pathogens that have become resistant to currently available agents is one strategy for combating resistant organisms. Several novel agents have either recently been approved, or are in various stages of development and are discussed in detail. It is unlikely that these agents will have a major impact on reducing the development and spread of MDR organisms. Consequently, the judicious use of currently available agents referred to as Antimicrobial Stewardship, and the development of and adherence to appropriate Infection Control policies and procedures are vital components in the management of these high-risk patients.

The impact of incorporating early rapid influenza diagnosis on hospital occupancy and hospital acquired influenza.

OBJECTIVE: To assess the impact of incorporating early rapid influenza diagnosis on antimicrobial usage, nosocomial influenza transmission, length of stay, and occupancy rates among hospitalized patients. SETTING: A 1,100 bed tertiary-care hospital in southern Israel. METHODS: We implemented early rapid detection of influenza with immediate communication of results. Using Orion methods, we compared the 2017-2018 influenza season to the prior season in our hospital and to the 2017-2018 occupancy rates at other Israeli hospitals. RESULTS: During the intervention season, 5,006 patients were admitted; 1,824 were tested for influenza, of whom 437 (23.9%) were positive. In the previous season, 4,825 patients were admitted; 1,225 were tested and 288 (23.5%) were positive. Time from admission to test report decreased from 35.5 to 18.4 hours (P < .001). Early discharge rates significantly increased, from 21.5% to 41.6% at 36 hours, from 37.2% to 54.5% at 48 hours, and from 66% to 73.2% at 72 hours. No increase in repeat ER visits, readmission, or mortality rates was observed. Hospital occupancy decreased by 10% compared to the previous year and was 26% lower than the national rate. Hospital-acquired influenza cases were reduced from 37 (11.4%) to 12 (2.7%) (P < .001). Antibiotic usage was reduced both before and after notification of test results by 16% and 12%, respectively. CONCLUSIONS: Implementing this intervention led to earlier discharge of patients, lower occupancy in medical wards, reduced antibiotic administration, and fewer hospital-acquired influenza events. This strategy is useful for optimizing hospital resources, and its implementation should be considered for upcoming influenza seasons.