Insights from genomic analysis of a novel Coxiella burnetii strain isolated in Israel.

The diagnosis of Q fever is challenging due to nonspecific symptoms and negative standard blood culture results. Serological testing through immunofluorescence assay (IFA) is the most commonly used method for diagnosing this disease. Polymerase chain reaction (PCR) tests can also be used to detect bacterial DNA if taken at an appropriate time. Once the presence of bacteria is confirmed in a sample, an enrichment step is required before characterizing it through sequencing. Cultivating C. burnetii is challenging as it can only be isolated by inoculation into cell culture, embryonated eggs, or animals. In this article, we describe the isolation of C. burnetii from a valve specimen in Vero cells. We conducted genome sequencing and taxonomy profiling of this isolate and were able to determine its taxonomic affiliation. Furthermore, Multispacer sequence typing (MST) analysis suggests that the infection originated from a local strain of C. burnetii found around northern Israel and Lebanon. This novel strain belongs to a previously described genotype MST6, harboring the QpRS plasmid, never reported in Israel.

The integration of Coxiella burnetii PCR testing in serum into the diagnostic algorithm of suspected acute Q fever in an endemic setting.

Serum polymerase chain reaction (PCR) for the detection of Coxiella burnetii DNA has been suggested for rapid Q fever diagnosis. We evaluated the role of PCR testing in serum in the diagnosis of acute Q fever in an endemic setting. We examined patients suspected of acute Q fever tested for C. burnetii-specific serum real-time PCR in a tertiary hospital between January 2019 toand December 2022. In the first half, PCR orders were consultation-based by infectious diseases specialists, while in the second half, they were guided by serology, positive IgM2, and negative IgG1 and IgG2, indicating early acute infection. Logistic regression analyzed independent predictors for positive PCR. PCR positivity rates were calculated using various clinical criteria in the diagnostic algorithm. Out of 272 patients, 13 (4.8%) tested positive and 130 exhibited serologically suspected early infection. Presentation during April-July and aspartate aminotransferase (AST) > 3× upper normal limit (UNL) were independently associated with positive PCR with an odds ratio (OR) = 15.03 [95% confidence interval (CI), 1.58-142.46], P = 0.018 and OR = 55.44 [95% CI, 6.16-498.69], P < 0.001, respectively. PCR positivity rate was 8.5% in serologically suspected early infection vs 1.4% in other serology, yielding OR = 6.4 [95% CI, 1.4-29.7], P = 0.009. Adding AST > 3× UNL increased OR to 49.5 [95% CI, 5.9-408.7], P ≤ 0.001 reducing required PCR tests for a single acute Q fever case from 11.8 to 3. Elevated AST in serologically suspected early Q fever is proposed to be used in a diagnostic stewardship algorithm integrating PCR in serum in an endemic setting. IMPORTANCE: Our study suggests in a diagnostic stewardship approach the integration of molecular testing (Coxiella burnetii targeted PCR) for the diagnosis of acute Q fever in a reliable time in the endemic setting. Integrating PCR detecting Coxiella burnetii in serum in routine testing of suspected early acute Q fever based on serology result increased the PCR positivity rate significantly. Adding increased transaminases optimizes PCR utility which is highly requested particularly in endemic areas.

Predictors of infectious foci on FDG PET/CT in Staphylococcus aureus bacteremia.

We looked for predicting factors for the detection of infectious foci on 18F-fluorodeoxyglucose-positron emission tomography in combination with computed tomography (FDG PET/CT) among patients with Staphylococcus aureus bacteremia (SAB) who participated in an interventional study that was conducted at Rambam Health Care Campus, between July 1, 2015 and February 1, 2019. The primary outcome was an infectious focus detected by FDG PET/CT. Independent predictors for detection of focal infection were identified using univariate followed by a logistic regression multivariate analysis. We included 149 patients with 151 separate episodes of SAB who underwent FDG-PET/CT. Focal infections were detected in 107 patients (70.8%). Independent predictors for focal infection detection were community acquisition of bacteremia with odds ratio (OR) 3.03 [95% confidence interval (CI) 1.04-8.77], p-0.042 and C reactive protein (CRP) with OR 1.09 [95% CI 1.04-1.14], p < 0.001. Primary bacteremia was inversely associated with focal infection detection with OR 0.27 [0.10-0.69], p = 0.007, as were the pre-scan blood glucose levels OR 0.9 [0.98-0.99], p-0.004. The latter stayed significant in the subgroup of patients with diabetes mellitus. To conclude, patients with community-acquired bacteremia or high CRP levels should be carefully investigated for focal infection. Patients who present with primary bacteremia seem to be at low risk for focal infection.

The Role of Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in the Management of Brucellosis: An Observational Cohort Study.

Background: Diagnosis of focal infection in brucellosis is important to direct optimal treatment. Fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) may be helpful in this aspect. Methods: The clinical and imaging data of all patients with brucellosis, who underwent FDG PET/CT as part of the investigation in Rambam Health Care Campus, where FDG PET/CT became the recommended imaging modality for suspected focal infection in brucellosis since 2016, were analyzed retrospectively. The detection of focal infection as well as management modification before and after FDG PET/CT were recorded. Results: FDG PET/CT was performed in 30 episodes of brucellosis occurring in 27 patients: 20 primary episodes and 10 suspected relapse episodes. The mean age of the patients was 50 ± 15.07 years. Focal disease was diagnosed in 18 of 30 (60%) episodes, of which 8 (26.6%) were diagnosed for the first time by FDG PET/CT, all of whom had spinal infection, with a concomitant additional focus in 5. Overall, multifocal disease was diagnosed in 10 of 18 (55.5%) of patients with focal disease. Management modification following FDG PET/CT was recorded in 17 of 30 (56.6%) episodes, mainly by treatment extension in spinal infection and withholding treatment in patients with suspected relapse but no evidence of active disease by FDG PET/CT. Conclusions: FDG PET/CT was found to be helpful in the diagnosis of focal infection in brucellosis. Multifocal disease seems more prevalent than previously described. The clinical impact of adding FDG PET/CT to the diagnostic workup of brucellosis should be evaluated in future studies.

Q fever screening among pregnant women with pre-term delivery in northern Israel: An observational study.

The relationship between Q fever, caused by Coxiella burnetii, and obstetrical complications is debatable. Since Q fever is endemic in Israel, we aimed to assess its seroprevalence and clinical characteristics in pre-term deliveries. Between 1 August 2017 and 31 December 2019, we conducted serological screening for C. burnetii in pregnant women who presented to Rambam Health Care Campus with pre-term delivery (before 37 weeks of gestation). Anti-C. burnetii antibodies were tested first by enzyme-linked immunosorbent assay for the detection of phase I-IgG, phase II-IgG and phase II-IgM. Positive results were confirmed by indirect immunofluorescence with titre determination. Seropositivity was classified into past, acute and chronic infection. Demographic and clinical data of mothers and neonates were collected and compared between seropositive and seronegative women. Out of 386 pregnant women screened for anti-C. burnetii antibodies, 16 (4.1%) were seropositive, of whom three were diagnosed with past, 12 with acute and one with chronic infection. A higher percentage of seropositive women were immunosuppressed, 2/16 (12.5%) compared with 7/370 (1.9%) in seronegative women, (p = .05). Neonates with small for gestational age were born to 2/16 (12.5%) seropositive women compared with 29/370 (7.8%) to seronegative women, (p = .35). The seroprevalence of Q fever among pregnant women with pre-term birth reached 4% in northern Israel. This high rate in an endemic setting encourages investigating the role of routine screening for Q fever during pregnancy. Special attention should be given to pregnant immunosuppressed women at risk for exposure to Q fever.

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.

FDG PET/CT in Cardiac Infection: Does It Matter? A Narrative Review.

The limited performance of echocardiography in specific infectious processes involving the heart led to the search for additional diagnostic tools. Fluorodeoxyglucose positron emission tomography computed tomography (FDG PET/CT) has been proposed for its diagnostic abilities in several infectious diseases including cardiac infections. A literature review of studies evaluating FDG PET/CT in native valve infective endocarditis (IE), prosthetic valve IE, cardiac implantable electrical device (CIED) infection, and left ventricular assist device (LVAD) infection is presented, focusing on studies published in recent years. Overall, in prosthetic valve endocarditis (PVE), FDG PET/CT demonstrate high sensitivity (73-93%) and specificity (80-95%), while in native valve endocarditis (NVE) the sensitivity is very low (22-68%), with high specificity (97-100%) similar to PVE. For CIED, LVAD infection, and transcatheter aortic valve implantation associated endocarditis, data come from small studies and show good diagnostic performance of FDG PET/CT. International guidelines are increasingly recommending FDG PET/CT for the diagnosis of specific conditions of cardiac infections. Beyond the diagnostic performance ability, few studies have evaluated the added benefit of FDG PET/CT in terms of clinical outcomes of patients with suspected cardiac infection. This should be the focus in future studies.

Risk factors for functional decline among survivors of Gram-negative bloodstream infection: A prospective cohort study.

OBJECTIVE: To identify risk factors for functional decline after hospitalization for Gram-negative bacteremia. PATIENTS AND METHODS: A prospective cohort study based on a randomized controlled trial conducted between January 1, 2013 and August 31, 2017 in Israel and Italy. Hospitalized patients with Gram-negative bacteremia who survived until day 90 and were not bedridden at baseline were included. The primary end point was functional decline at 90 days. RESULTS: Five hundred and nine patients were included. The median age of the cohort was 71 years (interquartile range [IQR], 60-80 years), 46.4% (236/509) were male and 352 of 509 (69%) patients were independent at baseline. Functional decline at 90 days occurred in 24.4% of patients (124/509). In multivariable analysis; older age (odds ratio [OR], 1.03; for an one-year increment, 95% confidence interval [CI] 1.01-1.05), functional dependence in instrumental activities of daily living at baseline (OR, 4.64; 95% CI 2.5-8.6), low Norton score (OR, 0.87; 95% CI 0.79-0.96) and underlying comorbidities: cancer (OR, 2.01; 95% CI 1.14-3.55) and chronic pulmonary disease (OR, 2.23 95% CI 1.12-4.42) and longer length of hospital stay (OR 1.09; for one-day increment, 95% CI 1.04-1.15) were associated with functional decline. Appropriate empirical antibiotic treatment was associated with lower rates of functional decline within 90 days (OR, 0.4; 95% CI 0.21-0.78). CONCLUSIONS: Patients surviving bloodstream infections have poor long term trajectories after clinical recovery and hospital discharge. This has vast implications for patients, their family members and health policy makers.

Vector-borne and zoonotic infections and their relationships with regional and socioeconomic statuses: An ID-IRI survey in 24 countries of Europe, Africa and Asia.

BACKGROUND: In this cross-sectional, international study, we aimed to analyze vector-borne and zoonotic infections (VBZI), which are significant global threats. METHOD: VBZIs' data between May 20-28, 2018 was collected. The 24 Participatingcountries were classified as lower-middle, upper-middle, and high-income. RESULTS: 382 patients were included. 175(45.8%) were hospitalized, most commonly in Croatia, Egypt, and Romania(P = 0.001). There was a significant difference between distributions of VBZIs according to geographical regions(P < 0.001). Amebiasis, Ancylostomiasis, Blastocystosis, Cryptosporidiosis, Giardiasis, Toxoplasmosis were significantly more common in the Middle-East while Bartonellosis, Borreliosis, Cat Scratch Disease, Hantavirus syndrome, Rickettsiosis, Campylobacteriosis, Salmonellosis in Central/East/South-East Europe; Brucellosis and Echinococcosis in Central/West Asia; Campylobacteriosis, Chikungunya, Tick-borne encephalitis, Visceral Leishmaniasis, Salmonellosis, Toxoplasmosis in the North-Mediterranean; CCHF, Cutaneous Leishmaniasis, Dengue, Malaria, Taeniasis, Salmonellosis in Indian Subcontinent; Lassa Fever in West Africa. There were significant regional differences for viral hemorrhagic fevers(P < 0.001) and tick-borne infections(P < 0.001), and according to economic status for VBZIs(P < 0.001). The prevalences of VBZIs were significantly higher in lower-middle income countries(P = 0.001). The most similar regions were the Indian Subcontinent and the Middle-East, the Indian Subcontinent and the North-Mediterranean, and the Middle-East and North-Mediterranean regions. CONCLUSIONS: Regional and socioeconomic heterogeneity still exists for VBZIs. Control and eradication of VBZIs require evidence-based surveillance data, and multidisciplinary efforts.

Screening for Q Fever in Patients Undergoing Transcatheter Aortic Valve Implantation, Israel, June 2018-May 2020.

Q fever infective endocarditis frequently mimics degenerative valvular disease. We tested for Coxiella burnettii antibodies in 155 patients in Israel who underwent transcatheter aortic valve implantation. Q fever infective endocarditis was diagnosed and treated in 4 (2.6%) patients; follow-up at a median 12 months after valve implantation indicated preserved prosthetic valvular function.

Q fever vertebral osteomyelitis among adults: a case series and literature review.

BACKGROUND: Q fever osteoarticular infections are a rare complication of the chronic form of Q fever. We aimed to characterize chronic Q fever vertebral osteomyelitis through our experience and a review of the literature. METHODS: Four adult patients with Q fever vertebral osteomyelitis diagnosed in a tertiary hospital in northern Israel between 2016 to 2020 are described. In addition, a 30 years' literature review of Q fever vertebral osteomyelitis, characterizing predisposing factors, clinical presentation, course of disease, treatment and outcomes, was performed. RESULTS: Thirty-four adult patients with Q fever vertebral osteomyelitis were identified. The vast majority were male (30/34, 88%) with a mean age of 67.2 ± 10 years. Involvement of the adjacent aorta, likely the origin of the infection, was observed in 23/34 (68%) of the patients, usually among patients with aortic graft or aneurysm. Clinical presentation was insidious and fever was frequently absent. Delayed diagnosis for months to years after symptoms onset was frequently reported. Vascular infections were managed with or without extraction of the infected aneurysm/aorta and graft placement. The outcome was variable with limited follow-up data in most cases. Patients were usually treated with prolonged antimicrobial therapy, most commonly doxycycline and hydroxychloroquine combination therapy. CONCLUSION: Q fever should be included in the differential diagnosis of vertebral osteomyelitis in endemic settings, in particular when concomitant adjacent vascular infection exists.

Q Fever Vertebral Osteomyelitis Complicating Vertebroplasty.

Query (Q) fever is a zoonotic bacterial infection caused by Coxiella burnetii. In a minority of patients, chronic disease can occur after acute infection. Endocarditis and infections of aneurysms or vascular prostheses are the most common forms of chronic Q fever in adults. We report a case of an elderly female patient with chronic Q fever vertebral osteomyelitis at the site of her previous cement vertebroplasty, complicated by paravertebral abscess. Patient treatment required prolonged drainage in addition to the long duration of antibiotic treatment by doxycycline and hydroxychloroquine. Osteomyelitis is a rare clinical presentation in adults with chronic Q fever. However, it is important to consider Q fever in the differential diagnosis of culture-negative osteomyelitis, especially in countries where C. burnetii is endemic, such as Israel.

Integration of FDG-PET/CT in the Diagnostic Workup for Staphylococcus aureus Bacteremia: A Prospective Interventional Matched-cohort Study.

BACKGROUND: Staphylococcus aureus bacteremia (SAB) is uniquely characterized by focal pyogenic complications that might not be apparent clinically. We investigated the benefit of adding fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) in the workup of patients with SAB. METHODS: In a matched-cohort study patients with SAB (intervention group) were prospectively recruited to undergo FDG-PET/CT 7-14 days after diagnosis. Treatment was directed by FDG-PET/CT findings. Clinical outcomes were compared with a control group of patients with SAB who had not undergone FDG-PET/CT, matched by age, Charlson score, methicillin susceptibility, and survival duration to FDG-PET/CT. The primary outcome was 90-day mortality. Residual confounding was controlled through regression analyses. RESULTS: During the study period 149 patients with 151 separate episodes of SAB underwent FDG-PET/CT and were compared with 150 matched patients with 151 SAB episodes. Patients in the intervention group acquired infections more frequently in the community and had less frequently solid malignancies and more frequently high-risk SAB. Ninety-day mortality in the intervention group was significantly lower than in the control group (21/151 [13.9%] vs 43/151 [28.5%], P = .002). The difference remained significant in a subgroup analysis of patients with community-onset infections without malignancy and among patients with low-risk SAB. Controlling for other risk factors for mortality, FDG-PET/CT performance among all patients was independently associated with lower mortality (OR, .39; 95% CI, .18-.84). Patients in the intervention group had longer duration of treatment and more focus control procedures performed compared with the control group. CONCLUSIONS: FDG-PET/CT in patients with SAB seems to improve survival through guidance of treatment duration and co-interventions.

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.

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.

Portraying infective endocarditis: results of multinational ID-IRI study.

Infective endocarditis is a growing problem with many shifts due to ever-increasing comorbid illnesses, invasive procedures, and increase in the elderly. We performed this multinational study to depict definite infective endocarditis. Adult patients with definite endocarditis hospitalized between January 1, 2015, and October 1, 2018, were included from 41 hospitals in 13 countries. We included microbiological features, types and severity of the disease, complications, but excluded therapeutic parameters. A total of 867 patients were included. A total of 631 (72.8%) patients had native valve endocarditis (NVE), 214 (24.7%) patients had prosthetic valve endocarditis (PVE), 21 (2.4%) patients had pacemaker lead endocarditis, and 1 patient had catheter port endocarditis. Eighteen percent of NVE patients were hospital-acquired. PVE patients were classified as early-onset in 24.9%. A total of 385 (44.4%) patients had major embolic events, most frequently to the brain (n = 227, 26.3%). Blood cultures yielded pathogens in 766 (88.4%). In 101 (11.6%) patients, blood cultures were negative. Molecular testing of vegetations disclosed pathogens in 65 cases. Overall, 795 (91.7%) endocarditis patients had any identified pathogen. Leading pathogens (Staphylococcus aureus (n = 267, 33.6%), Streptococcus viridans (n = 149, 18.7%), enterococci (n = 128, 16.1%), coagulase-negative staphylococci (n = 92, 11.6%)) displayed substantial resistance profiles. A total of 132 (15.2%) patients had cardiac abscesses; 693 (79.9%) patients had left-sided endocarditis. Aortic (n = 394, 45.4%) and mitral valves (n = 369, 42.5%) were most frequently involved. Mortality was more common in PVE than NVE (NVE (n = 101, 16%), PVE (n = 49, 22.9%), p = 0.042).

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.

Reemergence of Human Brucellosis in Israel.

BACKGROUND: The epidemiology of human brucellosis (HB) continues to evolve. OBJECTIVES: To describe the current epidemiology of HB in Israel in general and in the population at risk. METHODS: We calculated the incidence of HB in Israel for the period 2009-2015, overall and for the Arab population. Data are based on mandatory reporting of HB in Israel, defined clinically with either laboratory confirmation or epidemiological linkage to a laboratory-confirmed case. We mapped the geographic distribution of HB throughout the study period according to localities. We specified localities with high incidence (≥ 10 per 100,000 population) and mapped the distribution of dense localities with time. RESULTS: The incidence of HB in the general population in Israel increased sharply from 1.9 per 100,000 in 2009 to a peak of 7.3 per 100,000 in 2014. Each year, 95-100% of cases occurred among Arabs, thus the incidence in the Arab population increased from 10 per 100,000 in 2009 to 33.5 per 100,000 in 2014. Throughout this period 133 different localities reported at least one case of HB, and of these 20 were high-incidence localities during one year at least. During the period 2009-2013 the number of affected localities ranged from 35 to 44 per year and the disease was local, while in 2014 there were 82 localities distributed across the country. CONCLUSIONS: We demonstrate the importance of analyzing incidence in the population at risk for a disease. HB is an urgent public health issue in the Arab population in Israel, mandating an immediate and long-term eradication and control program.

Seven Versus 14 Days of Antibiotic Therapy for Uncomplicated Gram-negative Bacteremia: A Noninferiority Randomized Controlled Trial.

BACKGROUND: Gram-negative bacteremia is a major cause of morbidity and mortality in hospitalized patients. Data to guide the duration of antibiotic therapy are limited. METHODS: This was a randomized, multicenter, open-label, noninferiority trial. Inpatients with gram-negative bacteremia, who were afebrile and hemodynamically stable for at least 48 hours, were randomized to receive 7 days (intervention) or 14 days (control) of covering antibiotic therapy. Patients with uncontrolled focus of infection were excluded. The primary outcome at 90 days was a composite of all-cause mortality; relapse, suppurative, or distant complications; and readmission or extended hospitalization (>14 days). The noninferiority margin was set at 10%. RESULTS: We included 604 patients (306 intervention, 298 control) between January 2013 and August 2017 in 3 centers in Israel and Italy. The source of the infection was urinary in 411 of 604 patients (68%); causative pathogens were mainly Enterobacteriaceae (543/604 [90%]). A 7-day difference in the median duration of covering antibiotics was achieved. The primary outcome occurred in 140 of 306 patients (45.8%) in the 7-day group vs 144 of 298 (48.3%) in the 14-day group (risk difference, -2.6% [95% confidence interval, -10.5% to 5.3%]). No significant differences were observed in all other outcomes and adverse events, except for a shorter time to return to baseline functional status in the short-course therapy arm. CONCLUSIONS: In patients hospitalized with gram-negative bacteremia achieving clinical stability before day 7, an antibiotic course of 7 days was noninferior to 14 days. Reducing antibiotic treatment for uncomplicated gram-negative bacteremia to 7 days is an important antibiotic stewardship intervention. CLINICAL TRIALS REGISTRATION: NCT01737320.