Molecular features and transmission of NDM-producing Enterobacterales in Israeli hospitals.

OBJECTIVES: NDM-producing Enterobacterales (NDME) account for 34.9% of new carbapenemase-producing Enterobacterales cases in Israeli hospitals. The goals of this study were to characterize the genomic composition of NDME isolates and mobile genetic elements (MGEs) and to identify NDME transmission events (TEs). METHODS: The study was conducted at the Tel-Aviv Sourasky, Rambam and Sha'are-Zedek Medical Centers (TASMC, RMC and SZMC, respectively). All NDME isolates detected between January 2018 and July 2019 were included.Phylogenetic analysis was based on core-genome SNP distances. Core-genome distance of ≤5 SNPs between isolates from patients with overlapping hospitalization periods was suggestive of a potential TE. MGEs were classified by comparison of the blaNDM gene flanking regions. RESULTS: The study included 212 NDME isolates from 203 patients, including 104 isolates from TASMC, 30 isolates from RMC and 78 isolates from SZMC. The majority of isolates (n = 157; 74%) harboured the blaNDM-1 gene, followed by the blaNDM-5 (n = 48) and blaNDM-15 genes (n = 7). The most common NDME species were Klebsiella pneumoniae (n = 67), Escherichia coli (n = 65) and Enterobacter cloacae (n = 45), all showing a highly diverse clonal structure. Most blaNDM-1-harbouring isolates (134/157; 85%) were divided into nine different MGE modules, variably distributed across species and hospitals.The numbers of post-admission acquisition cases (n = 118) that could be linked to other cases by both molecular and epidemiological criteria were 13/58 (24.2%), 3/48 (6.3%) and 4/12 (33.3%) in TASMC, SZMC and RMC, respectively. CONCLUSIONS: The study depicted a complex and diverse population structure, suggesting that NDME had not spread via clonal expansion.

Predictive factors for focal disease in human brucellosis, an observational cohort study.

This retrospective cohort study aimed to identify predictors for focal disease in human brucellosis. The study included patients with brucellosis diagnosed between January 2000 and December 2021. Overall, 247 patients were identified. Focal disease was diagnosed in 64 (25.9%) patients. The most common focal infection was bone and joint in 56 patients (23.4%). Disease duration > 14 days was significantly associated with focal illness [OR = 2.2 (1.08-4.47), p = 0.030], although febrile illness was inversely associated with focal illness this did not reach statistical significance [OR = 0.46 (0.21-1.00), p = 0.050]. Focal brucellosis should be suspected in patients with prolonged illness.

Clinical and molecular features of NDM-producing Acinetobacter baumannii in a multicenter study in Israel.

BACKGROUND: NDM-producing Acinetobacter baumannii (NDMAb) were reported sporadically worldwide but little is known about the transmission, epidemiology and clinical features of NDMAb-infected patients. The goals of this study were to characterize (1) the epidemiology and clinical features of NDMAb-infected patients; (2) the microbiological and molecular features of NDMAb isolates and (3) the transmission networks of NDMAb within healthcare facilities. METHODS: The study was conducted at the Tel-Aviv Sourasky, Rambam and Sha'are-Zedek Medical centers (TASMC, RMC and SZMC, respectively) in Israel. All cases detected between January 2018 and July 2019 were included. Phylogenetic analysis was based on core genome SNP distances. Clonal transmission was defined according to molecular (≤ 5 SNP) and epidemiological criteria (overlapping hospital stay). NDMAb cases were compared at a ratio of 1:2 with non-NDM carbapenem-resistant A. baumannii (CRAb) cases. RESULTS: The study included 54 NDMAb-positive out of 857 CRAb patients, including 6/179 (3.3%) in TASMC, 18/441 (4.0%) in SZMC and 30/237 (12.6%) in RMC. Patients infected by NDMAb had similar clinical features and risk factors as patients with non-NDM CRAb. The length-of-stay was higher in NDMAb cases (48.5 days vs. 36 days, respectively, p = 0.097) and the in-hospital mortality was similarly high in both groups. Most isolates (41/54, 76%) were first detected from surveillance culture. The majority of isolates harbored the blaNDM-2 gene allele (n = 33), followed by the blaNDM-1 (n = 20) allele and the blaNDM-4 allele (n = 1). The majority of isolates were related within the ST level to other isolates in SZMC and RMC: 17/18 and 27/30 isolates, respectfully. The common ST's were the blaNDM-1 harboring ST-2 (n = 3) and ST-107 (n = 8) in SZMC and the blaNDM-2 harboring ST-103 in SZMC (n = 6) and in RMC (n = 27). All blaNDM alleles were located within a conserved mobile genetic environment flanked by the ISAb125 and IS91 family transposon. Clonal transmission was identified in most hospital-acquired cases in RMC and SZMC. CONCLUSION: NDMAb constitutes a minor part of CRAb cases and are clinically similar to non-NDM CRAb. Transmission of NDMAb occurs mostly by clonal spread.

Large-scale WGS of carbapenem-resistant Acinetobacter baumannii isolates reveals patterns of dissemination of ST clades associated with antibiotic resistance.

OBJECTIVES: To describe the population genetics and antibiotic resistance gene distribution of carbapenem-resistant Acinetobacter baumannii (CRAB) isolates causing infections in three Mediterranean countries. METHODS: Isolates were collected during the 2013-17 AIDA clinical trial in six hospitals in Israel, Greece and Italy. WGS, bioinformatic characterization and antibiotic resistance profiling were performed. RESULTS: In the 247 CRAB isolates characterized in this study, ST distribution varied by country: 29/31 (93.5%) Greek isolates, 34/41 (82.9%) Italian isolates and 70/175 (40.0%) Israeli isolates belonged to ST2. The identified ST2 isolates included eight distinct clades: 2C, 2D and 2H were significantly more common in Italy, while 2F was unique to Greece. The uncommon ST3 was not present among Greek isolates and constituted only 5/41 (12%) Italian isolates. On the other hand, it was much more common among Israeli isolates: 78/175 (44.6%) belonged to ST3. The vast majority of isolates, 240/247 (97.2%), were found to harbour acquired carbapenemases, primarily blaOXA-23. The chromosomal oxaAb (blaOXA-51-like) and ampC genes characteristic of this organism were also ubiquitous. Most (96.4%) ST3 isolates carried a broad-host-range plasmid IncP1α. CONCLUSIONS: The geographical differences in CRAB populations support the theory that clonal spread of CRAB leads to endemicity in hospitals and regions. The close association between antibiotic resistance genes and clades, and between plasmids and STs, suggest that de novo creation of MDR A. baumannii is rare. The clustering of antibiotic resistance genes and plasmids that is unique to each clade/ST, and nearly uniform within clades/STs, suggests that horizontal transmission is rare but crucial to the clade's/ST's success.

A high percentage of hospital-acquired neonatal bacteraemia but rare resistance to standard antibiotic regimens.

AIM: We examined community and hospital-acquired bacteraemia, namely bloodstream infections or meningitis, and looked at the clinical features and outcomes of cases. METHODS: The study comprised infants under 3 months of age, who were admitted to a tertiary referral centre in northern Israel with bacteraemia from 2010-2019. Causative pathogens, antibiotic susceptibility and mortality were retrospectively recorded. RESULTS: We identified 314 infants, 325 episodes of bacteraemia and 344 pathogens. Meningitis was identified in 22 (7.0%) infants. Hospital-acquired bacteraemia accounted for 84.8% of the 325 episodes. Coagulase-negative staphylococci (33.9%) was the most prevalent pathogen in the hospital-acquired cases, while Escherichia coli (37.2%) dominated the community-acquired cases. The susceptibility of Gram-negative early-onset sepsis cases to ampicillin-gentamicin or ampicillin-cefotaxime was 96% and 94.7% for hospital-acquired cases and 91.7% and 88% for community-acquired cases, respectively. Susceptibility to piperacillin-tazobactam or amikacin in late-onset sepsis were 92.8% and 98%, respectively, in hospital-acquired cases. The 30-day mortality was 5.7% in infants with hospital-acquired cases. Risk factors were Arab ethnicity (p < 0.028), haemodynamic instability (<0.001) and Gram-negative sepsis (0.043). CONCLUSION: Most cases of bacteraemia were acquired during hospitalisation and these accounted for the majority of the deaths. Resistance to standard antibiotic regimens was rare.

Oral Capsulized Fecal Microbiota Transplantation for Eradication of Carbapenemase-producing Enterobacteriaceae Colonization With a Metagenomic Perspective.

BACKGROUND: Carbapenemase-producing Enterobacteriaceae (CPE) infections lead to considerable morbidity and mortality. We assessed the potential of fecal microbiota transplantation (FMT) to eradicate CPE carriage and aimed to explain failure or success through microbiome analyses. METHODS: In this prospective cohort study, all consenting eligible CPE carriers received oral capsulized FMT for 2 days. Primary outcome was CPE eradication at 1 month, defined by 3 consecutive negative rectal swabs, the last also negative for carbapenemase gene by polymerase chain reaction. Comprehensive metagenomics analysis of the intestinal microbiome of donors and recipients before and after FMT was performed. RESULTS: Fifteen CPE carriers received FMT, 13 of whom completed 2 days of treatment. CPE eradication at 1 month was successful in 9/15 and 9/13, respectively. Bacterial communities showed significant changes in both beta and alpha diversity metrics among participants who achieved CPE eradication that were not observed among failures. Post-FMT samples' beta-diversity clustered according to the treatment outcome, both in taxonomy and in function. We observed a significant decrease in beta diversity in participants who received post-FMT antibiotics. Enterobacteriaceae abundance decreased in post-FMT samples of the responders but increased among failures. Functionally, a clear demarcation between responders (who were similar to the donors) and failures was shown, driven by antimicrobial resistance genes. CONCLUSIONS: Our study provides the biological explanation for the effect of FMT against CPE carriage. Decolonization of CPE by FMT is likely mediated by compositional and functional shifts in the microbiome. Thus, FMT might be an efficient strategy for sustained CPE eradication. CLINICAL TRIALS REGISTRATION: NCT03167398.

The impact of pneumococcal conjugate vaccine-13 on the incidence of pediatric community-acquired bacteremia.

The purpose of this study was to estimate the impact of pneumococcal conjugate vaccine-13 (PCV-13) introduction into the national immunization program in Israel on pneumococcal and non-pneumococcal pediatric community-acquired bacteremia (CAB). This is a retrospective cohort study, including children ≤ 18 years old with CAB, who were hospitalized in Rambam Health Care Campus, a tertiary medical center serving northern Israel, between the years 2004 and 2016. The proportional admission rate of pneumococcal bacteremia among all CAB events and the incidence of CAB and pneumococcal bacteremia per 1000 hospital admissions were compared between the pre- and post-pneumococcal vaccine eras. A total of 275 CAB events were identified. Common isolates were Streptococcus pneumoniae (SPn) (26.9%), Staphylococcus aureus (12.4%), Brucella spp. (11.6%), E. coli (10.9%), and Streptococcus pyogenes (5.8%). The pneumococcal bacteremia rate per 1000 hospital admissions decreased significantly from 1.59 to 0.6 (p < 0.001). The proportional pneumococcal bacteremia rate decreased from 55 (34.4%) to 19 (16.5%) (p 0.001). Penicillin resistance among pneumococcal isolates decreased dramatically from 50.9 to 5.3% (p < 0.001). The rate of bacteremia caused by other pathogens has not been changed significantly at the post-vaccination era (p 0.053). However, an increase in the incidence of S. pyogenes bacteremia from 1.9 to 11.3% (p < 0.001) was noticed. In addition, an outbreak of Brucella bacteremia occurred during the years 2015-2016. This study demonstrates the double positive effect of PVC-13 introduction: a sharp decrease in the proportional rate of pneumococcal bacteremia and in the resistance of SPn to penicillin. Also, there was a moderate decline in the incidence of CAB in exception to bacteremia caused by S. pyogenes. This trend was reversed due to a Brucella outbreak.

Community-acquired versus nosocomial Legionella pneumonia: factors associated with Legionella-related mortality.

Over the past decade, changes in the diagnosis and management of Legionella pneumonia occurred and risk factors for severe infection and increased mortality were identified. Previous reports found that nosocomial infection is associated with higher mortality while others showed no differences. We aimed to evaluate the differences in the clinical course and mortality rates between hospital-acquired pneumonia (HAP) and community-acquired pneumonia (CAP) caused by Legionella pneumophila. A retrospective cohort study of patients admitted due to Legionella pneumonia between January 2012 through November 2019 was conducted in a tertiary referral center (Rambam Health Care Campus, Haifa, Israel). The primary outcome was 30-day Legionella pneumonia-related mortality. A multivariable logistic regression was performed to determine whether a nosocomial infection is an independent predictor of mortality. One hundred nine patients were included. Seventy (64.2%) had CAP and 39 (35.8%) had HAP. The groups were comparable regarding age, gender, and comorbidities. Time to diagnosis was longer and the number of patients receiving initial empiric anti-Legionella spp. treatment was smaller in the HAP group (8 days [IQR 5.5-12.5] vs. 5 days [IQR 3-8], p < 0.001 and 65.5% vs. 78.6%, p = 0.003, respectively). Patients with HAP had higher 30-day mortality, 41% vs. 18.6%, p = 0.02. In a multivariable logistic regression model, only pneumonia severity index and nosocomial source were independently associated with increased mortality. HAP caused by Legionella spp. is independently associated with increased mortality when compared to CAP caused by the same pathogen. The possible reasons for this increased mortality include late diagnosis and delayed initiation of appropriate treatment.

The intraperitoneal bacteriology and antimicrobial resistance in acute appendicitis among children: a retrospective cohort study between the years 2007-2017.

This study aims to describe the microbiology and susceptibility profile of the intraperitoneal flora in complicated appendicitis. It is a retrospective cohort study including children < 18-year-old with pathologically confirmed appendicitis, from 2007 to 2017. It included 1466 children. Intraperitoneal samples were obtained from 655 (44.7%) patients, and 201 (30.7%) had positive culture with 395 pathogens. Gram-negative rods comprised 67.6%, Gram-positive cocci 21.5%, and anaerobes 10.9% of the isolates. Gram-positive cocci were detected in 67 (37.8%) patients. Milleri group Streptococci was the most frequently isolated Gram-positive (44.7%). The proportional rate of Milleri group Streptococci from Gram-positive cocci increased from 9.5 to 56.3% (P < 0.001, OR 12.214). Patients with Gram-positive cocci had longer hospital stay (mean 9.36 + 6.385 vs 7.72 + 4.582, P = 0.036, (CI -3.165, -0.105)) and more complicated disease (89.5% vs 78.4%, P = 0.045, OR 2.342). Patients with Milleri group Streptococci isolates readmitted more frequently (26.5% vs 13.2%, P = 0.05, OR 2.37). Resistance to amoxicillin-clavulanate, gentamicin, ceftazidime, piperacillin-tazobactam, and amikacin were detected in 29.1%, 6.5%, 2.3%, 1.2%, and 0.7% of the Gram-negative rods, respectively.Conclusion: The rates of Gram-positive cocci and particularly Milleri group Streptococci in peritoneal fluid are increasing. More complicated disease and longer hospital stay in Gram-positive cocci and higher readmission rate in Milleri group Streptococci. These emphasize the role of anti-Gram-positive antimicrobials. What is known: • Gram-negative rods are the main isolates in complicated appendicitis. • The choice of antibiotic regimen is an unsettled issue due to resistance. What is new: • Increased rate of Gram-positive cocci and Milleri group Streptococci. • More complicated disease, longer hospital stay, and higher readmission rate.

The epidemiology of Staphylococcus aureus bacteraemia in Israeli children: Community- vs hospital-acquired or healthcare related infections.

AIM: Incidences of Staphylococcus aureus bacteraemia (SAB) in Israeli children are unknown. The characteristics of SAB in children have not been evaluated. METHODS: SAB from children aged ≤18 years old, admitted to a tertiary hospital in Israel during 2002-2015, were included. The proportional rate of SAB was calculated per 1000 admissions. SAB were classified as community acquired (CA), hospital acquired (HA) and healthcare related (HCR). Patients' characteristics, antibiotic susceptibility and outcomes were assessed in each group. RESULTS: The rate of SAB was stable, 1.48 per 1000 admissions. HA, CA and HCR-SAB comprised 53%, 25% and 22%, respectively. Only 27/185 (14.6%) were caused by methicillin-resistant S aureus (MRSA): 22%, 6% and 5% of HA, CA and HCR-SAB, respectively. Central venous catheter, recent surgery, immunodeficiency and age <6 years were the main risk factors for HA and HCR-SAB (adjusted OR: 68.9, 7.5, 5.8 and 5.5, respectively). Treatment duration for CA was >21 days: and for HA and HCR, 14-20 days. All-cause in-hospital mortality and 30-day mortality were documented in 10 (5%) and 3 (2%) episodes, respectively. CONCLUSION: The rate of SAB; the proportions of CA, HA and HCR-SAB; and the proportion of MRSA was stable over the years. MRSA was mainly in HA-SAB. Thirty-day mortality was rare.

Evaluation of COVID-19 RT-qPCR Test in Multi sample Pools.

BACKGROUND: The recent emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to a current pandemic of unprecedented scale. Although diagnostic tests are fundamental to the ability to detect and respond, overwhelmed healthcare systems are already experiencing shortages of reagents associated with this test, calling for a lean immediately applicable protocol. METHODS: RNA extracts of positive samples were tested for the presence of SARS-CoV-2 using reverse transcription quantitative polymerase chain reaction, alone or in pools of different sizes (2-, 4-, 8-, 16-, 32-, and 64-sample pools) with negative samples. Transport media of additional 3 positive samples were also tested when mixed with transport media of negative samples in pools of 8. RESULTS: A single positive sample can be detected in pools of up to 32 samples, using the standard kits and protocols, with an estimated false negative rate of 10%. Detection of positive samples diluted in even up to 64 samples may also be attainable, although this may require additional amplification cycles. Single positive samples can be detected when pooling either after or prior to RNA extraction. CONCLUSIONS: As it uses the standard protocols, reagents, and equipment, this pooling method can be applied immediately in current clinical testing laboratories. We hope that such implementation of a pool test for coronavirus disease 2019 would allow expanding current screening capacities, thereby enabling the expansion of detection in the community, as well as in close organic groups, such as hospital departments, army units, or factory shifts.

Endovascular Infection with Kingella kingae Complicated by Septic Arthritis in Immunocompromised Adult Patient.

We report a case of Kingella kingae endovascular infection in an immunocompromised elderly patient in Israel who had culture-negative septic arthritis. This case highlights potential sources of metastatic infection other than infective endocarditis, and emphasizes the need for molecular diagnostic methods in detection of pathogens in culture-negative septic arthritis in immunocompromised patients.

EttA is likely non-essential in Staphylococcus aureus persistence, fitness or resistance to antibiotics.

BACKGROUND: Tolerance to antibiotics and persistence are associated with antibiotic treatment failures, chronic-relapsing infections, and emerging antibiotic resistance in various bacteria, including Staphylococcus aureus. Mechanisms of persistence are largely unknown, yet have been linked to physiology under low-ATP conditions and the metabolic-inactive state. EttA is an ATP-binding cassette protein, linked in Eschrechia coli to ribosomal hibernation and fitness in stationary growth phase, yet its role in S. aureus physiology is unknown. RESULTS: Using whole genome sequencing (WGS) of serial clinical isolates, we identified an EttA-negative S. aureus mutant (ettAstop), and its isogenic wild-type counterpart. We used these two isogenic clones to investigate the role of ettA in S. aureus physiology in starvation and antibiotic stress, and test its role in persistence and antibiotic tolerance. ettAstop and its WT counterpart were similar in their antibiotic resistance profiles to multiple antibiotics. Population dynamics of ettAstop and the WT were similar in low-nutrient setting, with similar recovery from stationary growth phase or starvation. Supra-bacteriocidal concentration of cefazolin had the same killing effect on ettAstop and WT populations, with no difference in persister formation. CONCLUSIONS: Lack of ettA does not affect S. aureus antibiotic resistance, beta-lactam tolerance, resilience to starvation or fitness following starvation. We conclude the role of ettA in S. aureus physiology is limited or redundant with another, unidentified gene. WGS of serial clinical isolates may enable investigation of other single genes involved in S. aureus virulence, and specifically persister cell formation.

Routine comprehensive Aspergillus screening of bronchoalveolar lavage samples in lung transplant recipients.

BACKGROUND: Invasive aspergillosis is a significant cause of morbidity and mortality in lung transplant recipients (LTRs). Early diagnosis may improve outcome, yet is challenging. We assessed the diagnostic yield of a routine, comprehensive, prospectively employed Aspergillus screening strategy in LTRs. METHODS: During a 6-month period, all bronchoalveolar lavage (BAL) samples (including post-transplant surveillance) obtained from LTRs at our center were routinely tested for Aspergillus PCR, galactomannan (GM), and fungal culture. Invasive aspergillosis (IA) was defined using EORTC/MSG and ISHLT criteria for proven and probable aspergillosis. RESULTS: Ninety-five consecutive BAL samples were tested. PCR, GM, and fungal culture were positive in 28.4%, 30.6%, and 7.4%, respectively. Five cases of IA (two proven, three probable) were identified. Fungal culture failed to detect 40% of IA cases, which were detected by a positive PCR and/or GM. However, the majority of positive PCR samples represented colonization (59.3%). Sensitivity of PCR, GM, and culture for IA was 80%, 60%, and 60%, respectively, and specificity was 74%, 71%, and 96%. CONCLUSIONS: In LTRs, a routine prospectively employed screening strategy in which all BAL samples were screened for Aspergillus PCR and GM, detected aspergillosis cases that were otherwise missed by a false-negative fungal culture, but resulted in more cases of colonization being detected. Clinical judgment is thus warranted to avoid unnecessary treatment of colonization.

Cold sub-atmospheric and atmospheric pressure plasma for the treatment of Trichophyton rubrum onychomycosis: An in-vitro study.

Previous studies have suggested the applicability of cold atmospheric pressure plasma for the treatment of onychomycosis. Whether delivering cold plasma in sub-atmospheric pressure would be beneficial for this purpose is yet to be established. The current study aimed to evaluate efficacy of cold sub-atmospheric and atmospheric pressure plasma in Trichophyton rubrum growth inhibition. Bovine nails infected with T. rubrum were treated by a cold air plasma device, which enables utilizing plasma in sub-atmospheric pressures (Low = 100 millibar; High = 300 millibar) or atmospheric pressure. The infected foci were exposed to the plasma source directly or indirectly. Treatment with high sub-atmospheric pressure setting achieved T. rubrum growth reduction of 94.0% and 73.0%, for direct and indirect exposure to the plasma source, respectively (P < .001). Low sub-atmospheric pressure setting achieved similar T. rubrum growth reduction of 86.2% for direct exposure to the plasma source (P < .001), but only marginally significant 58.8% reduction rate for indirect exposure to the plasma source (P = .056). None statistically significant fungal growth reduction was attained with the use of atmospheric pressure setting. Cold plasma was shown to effectively inhibit T. rubrum nail growth, with sub-atmospheric pressure setting achieving better outcome than atmospheric pressure.

Rapid phenotypic antimicrobial susceptibility testing using nanoliter arrays.

Antibiotic resistance is a major global health concern that requires action across all sectors of society. In particular, to allow conservative and effective use of antibiotics clinical settings require better diagnostic tools that provide rapid determination of antimicrobial susceptibility. We present a method for rapid and scalable antimicrobial susceptibility testing using stationary nanoliter droplet arrays that is capable of delivering results in approximately half the time of conventional methods, allowing its results to be used the same working day. In addition, we present an algorithm for automated data analysis and a multiplexing system promoting practicality and translatability for clinical settings. We test the efficacy of our approach on numerous clinical isolates and demonstrate a 2-d reduction in diagnostic time when testing bacteria isolated directly from urine samples.

Clinical Spectrum, Diagnosis and Outcome of Rare Fungal Infections in Patients with Hematological Malignancies: Experience of 15-Year Period from a Single Tertiary Medical Center.

BACKGROUND: Patients with hematological malignancies and allogeneic hematopoietic stem-cell transplant recipients carry a high risk of rare (non-Aspergillus molds and non-Candida yeasts) invasive fungal infections (IFI). METHODS: We retrospectively evaluated and described the patient profile, clinical manifestations, isolated species, treatment and outcome of patients with hematological malignancies diagnosed with these rare IFIs during 15 years in a large single hemato-oncology center. RESULTS: Eighty-seven patients with hematological malignancies treated in our center had at least one positive culture or molecular identification of a rare fungus. Ninety-three isolates were considered the etiological agents of the infection. The most common underlying hematological malignancy was acute myeloid leukemia, 36 patients (41.4%). Eighty patients (91%) received chemotherapy less than 30 days prior to IFI diagnosis. The most frequent site of infection was the respiratory tract: 34 patients (39%) had pulmonary and 19 patients (22%) had a sinusal or nasopharyngeal infections. Disseminated infection, defined as positive blood cultures or parallel infection in multiple organ systems, was documented in 20 patients (23%). The most common fungal species were Fusarium (35%) and Zygomycetes (25%). Coinfection with more than one fungus was noted in 20 patients (23%). Forty-seven of 87 patients (54%) in this study died within 90 days of IFI diagnosis. CONCLUSIONS: Rare IFIs in patients with hematological malignancy become increasingly frequent. Early identification with traditional and molecular methods is important in management of these patients.

The association between fluconazole dose and MIC with mortality and persistence in candidemia.

To evaluate the association between fluconazole exposure parameters and clinical outcomes in patients with candidemia. We retrospectively included all adults with candidemia in a single center from January 2009 to December 2017, treated initially with fluconazole for fluconazole-susceptible candidemia. We assessed the association between fluconazole exposure parameters and 30-day mortality or 14-day clinical failure, a composite of mortality at day 14 or persistent candidemia ≥ 72 h, in all patients and in patients with C. glabrata candidemia. During the study period, 158 patients fulfilled the inclusion criteria. Main species were C. albicans 66 (41.8%), C. glabrata 35 (22.2%), and C. parapsilosis 31 (19.6%). Sixty patients (38%) died within 30 days. Sixty-one patients (38.6%) experienced 14-day failure. In 30-day survivors, the median AUC24/MIC was 2279 [398, 5989] versus 1764 [238, 6714] h in non-survivors, p = 0.75. Median fluconazole MIC was 0.75 [0.25, 4] and 1 [0.22, 5.50] mg/L, p = 0.54, respectively. Similar non-significant differences were found for other fluconazole exposure parameters and in the 14-day clinical failure analysis. For C. glabrata, a higher AUC24/MIC was observed among 30-day survivors with a median of 230 [77, 539] compared to 96 [75, 164] h in non-survivors, p = 0.008, in parallel with a trend for lower MIC values (median 7 [1, 2] versus 16 [8, 24] mg/L, p = 0.06, respectively). Currently used fluconazole dosing has no association with clinical outcome in Candida with low MIC values. For Candida species with high MICs, attention to dosing is needed.

Treatment Outcomes of Stenotrophomonas maltophilia Bacteremia in Critically Ill Children: A Multicenter Experience.

OBJECTIVES: Stenotrophomonas maltophilia is a gram-negative opportunistic bacterium that may cause a myriad of clinical diseases in immunocompromised individuals. We aimed to describe the clinical characteristics, risk factors, mortality, and treatment of S. maltophilia bacteremia in critically ill children, a topic on which data are sparse. DESIGN: A multicenter observational retrospective study in which medical charts of critically ill children with S. maltophilia bacteremia were reviewed between 2012 and 2017. SETTING: Data were collected from each of the four largest PICUs nationwide, allocated in tertiary medical centers to which children with complex conditions are referred regularly. PATIENTS: A total of 68 suitable cases of S. maltophilia bacteremia were retrieved and reviewed. MEASUREMENTS AND MAIN RESULTS: The total occurrence rate of S. maltophilia isolation had increased significantly during the study period (r = 0.65; p = 0.02). The crude mortality was 42%, and the attributed mortality was 18%. Significant risk factors for mortality were a longer length of hospital stay prior to infection (33 d in nonsurvivors vs 28 in survivors; p = 0.03), a nosocomial source of infection (p = 0.02), presentation with septic shock (p < 0.001), and treatment with chemotherapy (p = 0.007) or carbapenem antibiotics (p = 0.05) prior to culture retrieval. On multivariate analysis, septic shock (odds ratio, 14.6; 95% CI, 1.45-147.05; p = 0.023) and being treated with chemotherapy prior to infection (odds ratio, 5.2; 95% CI, 1.59-17.19; p = 0.006)] were associated with mortality. The combination of ciprofloxacin, trimethoprim-sulfamethoxazole, and minocycline resulted in the longest survival time (p < 0.01). CONCLUSIONS: The significant attributed mortality associated with S. maltophilia bacteremia in critically ill children calls for an aggressive therapeutic approach. The findings of this investigation favor a combination of trimethoprim-sulfamethoxazole, ciprofloxacin, and minocycline.

Risk Factors for Non-Albicans Candidemia Focusing on Prior Antifungal and Immunosuppressive Therapy.

BACKGROUND: With the widespread use of antifungal agents, the frequency of non-albicans Candida (NAC) blood-stream infections (BSI) is increasing. OBJECTIVES: To describe the epidemiology, clinical manifestations, and risk factors for NAC BSI, focusing on prior antifungal and immunosuppressive therapy. METHODS: The authors conducted an observational, retrospective cohort study among adult patients with candidemia at the Rambam Health Care Campus, a tertiary medical center in Israel, between 2009 and 2015. Comparisons between patients with Candidemia albicans and NAC candidemia were performed. Regression analysis, with NAC BSI as the dependent variable and significant risk factors for NAC as independent variables, was performed. RESULTS: A total of 308 episodes of candidemia were included. C. albicans was isolated in 30.8% of patients (95/308), while NAC spp. were isolated in the rest. Significant independent risk factors for NAC included immunosuppression therapy (odds ratio [OR] 0.38, 95% confidence interval [95%CI] 0.19-0.76) and previous azole use (OR 0.2, 95%CI 0.06-0.710). The interaction between prior azole and immunosuppression therapy in the model was not significant, and after its inclusion in the model only immunosuppression remained significantly associated with NAC. In the subgroup of patients who did not receive prior azoles, immunosuppression therapy, neutropenia, and bone marrow transplantation were significantly associated with NAC. CONCLUSIONS: Independent of previous azole treatment, immunosuppressive therapy was a significant risk factor for NAC in our cohort.