ABSTRACTForgiveness, a process of relinquishment of resentment, hostility, and anger toward an offender or self, is understudied among people living with HIV. This study examined the experience and process of forgiving the person who allegedly transmitted HIV, among people living with HIV. In-depth interviews were conducted with 14 people living with HIV aged 25 or older, diagnosed at least three years before the study. Three main themes emerged: "Anger is a poison": between forgiveness and unforgiveness; "I gave up the drive to suffer": the meaning of forgiveness; and "Forgiving is like building a building": phases of the forgiveness process between forgiveness and unforgiveness. This study revealed cognitive and emotional processes and phases of forgiveness. Forgiveness-focused interventions for people living with HIV are suggested.

Highly variable estimates of COVID-19-associated fungal diseases (IFDs) have been reported. We aimed to determine the incidence of clinically important fungal diseases in hospitalized COVID-19 patients during the first year of the pandemic. We performed a multicenter survey of IFDs among patients hospitalized with COVID-19 in 13 hospitals in Israel between February 2020 and May 2021. COVID-19-associated pulmonary mold disease (PMD) and invasive candidiasis (IC) were defined using ECMM/ISHAM and EORTC/MSG criteria, respectively. Overall rates of IC and PMD among patients with critical COVID-19 were 10.86 and 10.20 per 1000 admissions, respectively, with significant variability among medical centers. PMD rates were significantly lower in centers where galactomannan was a send-out test versus centers with on-site testing (p = 0.035). The 30-day mortality rate was 67.5% for IC and 57.5% for PMD. Treatment with an echinocandin for IC or an extended-spectrum azole for PMD was associated with significantly lower mortality rates (adjusted hazard ratio [95% confidence interval], 0.26 [0.07–0.91] and 0.23 [0.093–0.57], respectively). In this multicenter national survey, variable rates of PMD were associated with on-site galactomannan testing, suggesting under-detection in sites lacking this capacity. COVID-19-related IFDs were associated with high mortality rates, which were reduced with appropriate antifungal therapy.

BACKGROUND:We aimed to review the current state, challenges, and needs of antimicrobial stewardship programs (ASPs) in adult solid organ transplantation (SOT) centers in Israel.METHODS:We conducted a survey using electronic questionnaires sent during February 2022 to infectious disease (ID) consultants of SOT centers, encompassing general and organ-specific ASP issues.RESULTS:All six centers performing adult SOTs in Israel participated. The institutional ASPs in all centers included SOT recipients, and five centers had specific stewardship activities targeting SOT recipients. ASP activities were performed by ID consultants in all centers, with clinical pharmacists in most. ASP protocols and activity scope were highly variable. Formulary restriction with pre-authorization was used in all centers. Antibiotic allergy was addressed in ASP guidelines in half of the centers. Peri-transplantation antibiotic, antifungal, and antiviral prophylactic regimens varied based on center, transplanted organ, and patient risk group. Approaches to surveillance cultures, diagnosis and treatment of various graft infections were also variable. ASP outcome measurement was not performed in all centers. The main challenges and barriers to successful ASP implementation were difficulty in defining appropriate durations of therapy for certain infections, high rates of antimicrobial resistance (AMR), and lack of dedicated ASP teams.CONCLUSION:Antimicrobial stewardship in SOT centers in Israel is performed by ID consultants and practices vary. Challenges are related to high AMR rates, insufficient evidence to support practices, lack of dedicated ASP teams, and lack of outcome measurement. There is an urgent need to establish a national collaborative program including all SOT centers.

Majority of transplant recipients did not develop an appreciable humoral response following SARS-CoV-2 vaccine, in contrast to dialysis patients and healthy individuals. We analyzed the serologic response to BNT162b2 (Pfizer-BioNTech) vaccine in a cohort of 19 kidney transplant recipients, vaccinated prior to transplantation, compare to 109 recipients vaccinated after transplantation, and to 39 healthcare workers, by determining the level of anti-spike antibodies after transplantation. All controls and 17 of 19 (90%) of recipients vaccinated before transplant were seropositive, while only 49 of 109 (45%) recipients vaccinated post-transplant had positive serology (P < .001). Median anti-spike IgG in the group of kidney transplant recipients vaccinated after transplantation (10.7 AU/ml, [IQR 0-62.5]) was lower than the patients vaccinated before transplantation (66.2 AU/ml [21.6-138]), which was significantly lower than in the controls (156 AU/ml [99.7-215.5]). Negative humoral response was associated with vaccination post transplantation (odds ratio 22.4), older age (OR = 1.04), and longer time on dialysis (OR = 1.02), while higher lymphocyte count at time of vaccination was protective (OR = .52). Our findings of sustained superior humoral response to SARS-CoV-2 vaccine in kidney transplant recipients vaccinated prior to transplantation strongly support the recommendations of SARS-CoV-2 vaccination of transplant candidates, especially those younger than 60 years.

Bartonella spp., mostly Bartonella quintana and B. henselae , are a common cause of culture-negative endocarditis. Serology using immunofluorescence assay (IFA) and PCR performed on cardiac tissues are the mainstays of diagnosis.

Background & Aims: Two SARS-CoV-2 mRNA vaccines were approved to prevent COVID-19 infection, with reported vaccine efficacy of 95%. Liver transplant (LT) recipients are at risk of lower vaccine immunogenicity and were not included in the registration trials. We assessed vaccine immunogenicity and safety in this special population. Methods: LT recipients followed at the Tel-Aviv Sourasky Medical Center and healthy volunteers were tested for SARS-CoV-2 IgG antibodies directed against the Spike-protein (S) and Nucleocapsid-protein (N) 10-20 days after receiving the second Pfizer-BioNTech BNT162b2 SARS-CoV-2 vaccine dose. Information regarding vaccine side effects and clinical data was collected from patients and medical records. Results: Eighty LT recipients were enrolled. Mean age was 60 years and 30% were female. Twenty-five healthy volunteer controls were younger (mean age 52.7 years, p = 0.013) and mostly female (68%, p = 0.002). All participants were negative for IgG N-protein serology, indicating immunity did not result from prior COVID-19 infection. All controls were positive for IgG S-protein serology. Immunogenicity among LT recipients was significantly lower with positive serology in only 47.5% (p < 0.001). Antibody titer was also significantly lower in this group (mean 95.41 AU/ ml vs. 200.5 AU/ml in controls, p < 0.001). Predictors for negative response among LT recipients were older age, lower estimated glomerular filtration rate, and treatment with high dose steroids and mycophenolate mofetil. No serious adverse events were reported in either group. Conclusion: LT recipients developed substantially lower immunological response to the Pfizer-BioNTech SARS-CoV-2 mRNA-based vaccine. Factors influencing serological antibody responses include age, renal function and immunosuppressive medications. The findings require re-evaluation of vaccine regimens in this population. Lay summary: The Pfizer-BioNTech BNT162b2 SARS-CoV-2 vaccine elicited substantially inferior immunity in liver transplant recipients. Less than half of the patients developed sufficient levels of antibodies against the virus, and in those who were positive, average antibody levels were 2x less compared to healthy controls. Factors predicting non-response were older age, renal function and immunosuppressive medications. (C) 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

During 2011-16, HIV outbreaks occurred among people who inject drugs (PWID) in Canada (southeastern Saskatchewan), Greece (Athens), Ireland (Dublin), Israel (Tel Aviv), Luxembourg, Romania (Bucharest), Scotland (Glasgow), and USA (Scott County, Indiana). Factors common to many of these outbreaks included community economic problems, homelessness, and changes in drug injection patterns. The outbreaks differed in size (from under 100 to over 1000 newly reported HIV cases among PWID) and in the extent to which combined prevention had been implemented before, during, and after the outbreaks. Countries need to ensure high coverage of HIV prevention services and coverage higher than the current UNAIDS recommendation might be needed in areas in which short acting drugs are injected. In addition, monitoring of PWID with special attention for changing drug use patterns, risk behaviours, and susceptible subgroups (eg, PWID experiencing homelessness) needs to be in place to prevent or rapidly detect and contain new HIV outbreaks.

Human immunodeficiency virus (HIV) infection was traditionally considered an absolute contraindication for kidney transplantation. After the introduction of ART, several studies have demonstrated comparable patient and graft outcomes between HIV-negative and HIV-positive kidney recipients. The US Congress passed the HIV Organ Policy Equity (HOPE) Act in 2013, which permits research in the area of HIV-positive to HIV-positive transplantation. HIV-infected living donation is also permitted under the HOPE Act. However, there is a concern regarding the safety of kidney donation in an HIV-infected person, given the risk of renal disease associated with HIV infection. We report here the case of successful kidney transplantation from HIV-positive living donor to HIV-positive recipient performed in our center on July 2012. To the best of our knowledge, this is the earliest case done in this medical context to be reported in the literature, therefore, potentially carrying several important messages to the transplantation community. In the present case, the living-donor kidney transplant was performed between a married couple infected with same strain of HIV-1, both on effective ART with efficiently suppressed viral replication and satisfactory pre-transplantation immune status.

OBJECTIVESubtype-A HIV was introduced into Israel in the mid-1990s, predominantly by immigrants from the former Soviet Union (FSU) infected via intravenous drug use (IVDU). HIV subsequently spread beyond the FSU-IVDU community. In 2012, a mini-HIV outbreak, associated with injection of amphetamine cathinone derivatives, started in Tel Aviv, prompting public health response. To assess current trends and the impact of the outbreak and control measures, we conducted a phyloepidemiologic analysis.METHODDemographic and clinical records and HIV sequences were compiled from 312 subtype-A HIV-infected individuals attending the Tel-Aviv Sourasky Medical Center between 2005-2016, where >40% of all subtype-A HIV-infected individuals in Israel are undergoing care. Molecular evolutionary genetics analysis (MEGA) and ayesian evolutionary analysis sampling trees (BEAST) programs were implemented in a phylogenetic analysis of pol sequences. Reconstructed phylogenies were assessed in the context of demographic information and drug-resistance profiles. Clusters were identified as sequence populations with posterior probability ≥0.95 of having a recent common ancestor.RESULTSAfter 2010, the subtype-A epidemic acquired substantial phylogenetic structure, having been unrecognized in studies covering the earlier period. Nearly 50% of all sequences were present in 11 distinct clusters consisting of 4-43 individuals. Cluster composition reflected transmission across ethnic groups, with men who have sex with men (MSM) playing an increasing role. The cathinone-associated cluster was larger than previously documented, containing variants that continued to spread within and beyond the IVDU community.CONCLUSIONSPhyloepidemiologic analysis revealed diverse clusters of HIV infection with MSM having a central role in transmission across ethic groups. A mini outbreak was reduced by public health measures, but molecular evidence of ongoing transmission suggests additional measures are necessary.

BackgroundFebrile neutropenia may be a sign of severe infection and is associated with significant morbidity and mortality in high-risk patients with hematologic malignancies. Extended infusion of β-lactam antibiotics is associated with greater clinical response than is bolus infusion in nonneutropenic critically ill patients, but data are lacking for febrile neutropenic patients.MethodsWe designed a single-center, nonblinded, randomized trial to compare extended infusion (4 hours) and bolus infusion (30 minutes) of piperacillin-tazobactam or ceftazidime in high-risk patients with febrile neutropenia. The primary endpoint was overall response on day 4, defined as the combination of resolution of fever, sterile blood cultures, resolution of clinical signs and symptoms, and no need for a change in the antibiotic regimen. Outcome was adjudicated by investigators blinded to treatment allocation.ResultsOf 123 enrolled patients, 105 had febrile neutropenia and were included in the intention-to-treat analysis: 47 in the extended infusion arm and 58 in the bolus infusion arm. Overall response occurred in 35 (74.4%) patients treated with extended infusion and 32 (55.1%) patients treated with bolus infusion (P = .044). The superiority of extended infusion was greatest for patients with clinically documented infections (overall response, 68.4% [13/19] vs 35.7% [10/28]; P = .039) and specifically for those with pneumonia (80% [4/5] vs 0% [0/8]; P = .007).ConclusionsExtended infusion of β-lactams is associated with superior treatment outcomes compared with bolus infusion for high-risk patients with febrile neutropenia. The benefit of extended β-lactam infusion may be greatest for patients with pulmonary infections.Clinical Trials RegistrationNCT02463747.

Background: Neutropenic fever is a life-threatening condition which is common in patients with hematologic malignancies, and prompt initiation of appropriate antibiotics is of great importance.Empirical treatment includes monotherapy with a beta-lactam containing anti-pseudomonal activity. Theoretically, time-dependent antibiotics are most active when administered as a continuous infusion, but evidence is lacking in cases of febrile neutropenia. This study examines the optimal dosing regimen (bolus infusion vs. prolonged 4 hour-infusion) for high risk patients undergoing hematopoietic cell transplantation or patients with acute leukemia and febrile neutropenia. Methods: This was a single center, prospective, unblinded randomized study, of 123 hospitalized hematologic patients enrolled between July 2015 and March 2017. The primary outcome was a successful response to treatment, defined as the combination of- defervescence at 96 hours after initiation of broad spectrum beta-lactams (pipracillin/tazobactam or ceftazidime) or before, sterile cultures after 72-96 hours, and no requirement of additional aminoglycoside therapy after 48 hours. Secondary outcomes included breakthrough fever or additional infection after 5 days from initiation of treatment, death within 30 days of study enrollment, duration of hospitalization, duration of neutropenia, occurrence of renal failure (doubling of serum creatinine levels) within 5 days, and requirement for noradrenaline due to hypotension. Patients were randomized using a computerized random number program and allocation was concealed by sequentially numbered sealed and opaque envelopes. All patients signed informed consent and the study was approved by the Tel Aviv Medical Center Institutional Review Board. Results: 123 patients were randomized to bolus infusion (n=63) and prolonged infusion (n=60). Febrile neutropenia occurred in 87% of the patients, and these patients were eligible for the intention-to-treat analysis (ITT). 73% of the patients were given at least one dose of antibiotic according to the allocation arm and were eligible for the per-protocol analysis, Figure . The patients9 baseline characteristics were well-balanced between the 2 groups, Table 1 . In the ITT analysis ( Table 2 ), there was a higher success rate in patients allocated to the prolonged infusion arm, compared to those allocated to the bolus infusion arm (76% vs. 55%, p= .03). This was also true for the subgroups of patients with microbiologically documented infections (MDI) - (55.6% vs. 7.7%, p=.013) and blood stream infections, (BSI) - (67% vs. 8.3%, p=.009). Similarly, in the per-protocol analysis, the success rate was higher in patients allocated to the prolonged infusion arm who had MDI (62.5% vs. 12.5%, p=.039) or BSI (80% vs. 14.3%, p=.023). There was no difference in the secondary endpoint outcomes between the 2 groups. 30-day death rate was similarly low in both groups. Prolonged beta-lactam infusion was associated with significantly higher treatment success in a logistic regression model that included either BSI (odds ratio of 2.4, 95% CI 0.97-6.1, p=.058) or MDI (OR 2.8, 95% CI 1.1-7.4, p=.032) . Conclusions: This is the first randomized study showing superior treatment outcomes in patients with high-risk febrile neutropenia treated with prolonged versus bolus beta-lactam infusion. Optimization of beta-lactam dosing is a widely available and cost-effective strategy to improve treatment outcomes in patients with high risk febrile neutropenia. Disclosures No relevant conflicts of interest to declare.

ABSTRACT Detection of low-abundance drug resistance mutations (DRMs) of HIV-1 is an evolving approach in clinical practice. Ultradeep pyrosequencing has shown to be effective in detecting such mutations. The lack of a standardized commercially based assay limits the wide use of this method in clinical settings. 454 Life Sciences (Roche) is developing an HIV ultradeep pyrosequencing assay for their benchtop sequencer. We assessed the prototype plate in the clinical laboratory. Plasma samples genotyped by the standardized TruGene kit were retrospectively tested by this assay. Drug-treated subjects failing therapy and drug-naive patients were included. DRM analysis was based on the International AIDS Society USA DRM list and the Stanford algorithm. The prototype assay detected all of the DRMs detected by TruGene and additional 50 low-abundance DRMs. Several patients had low-abundance D67N, K70R, and M184V reverse transcriptase inhibitor mutations that persisted long after discontinuation of the drug that elicited these mutations. Additional patient harbored low-abundance V32I major protease inhibitor mutation, which under darunavir selection evolved later to be detected by TruGene. Stanford analysis suggested that some of the low-abundance DRMs were likely to affect the resistance burden in these subjects. The prototype assay performs at least as well as TruGene and has the advantage of detecting low-abundance drug resistance mutations undetected by TruGene. Its ease of use and lab-scale platform will likely facilitate its use in the clinical laboratory. The extent to which the detection of low-abundance DRMs will affect patient management is still unknown, but it is hoped that use of such an assay in clinical practice will help resolve this important question.

BACKGROUND:Outbreaks of syphilis have been described among men who have sex with men (MSM) in many western urban communities in the last few years.OBJECTIVES:To describe the first reported outbreak of syphilis among MSM in Israel within a decade of a constant increase in human immunodeficiency virus (HIV) prevalence.METHODS:All patients diagnosed with syphilis were contacted and asked about their sexual behavior, substance use and previous infections. All were tested for HIV and a phylogenetic analysis was performed.RESULTS:A total of 23 (59%) of all 39 male patients diagnosed with primary or secondary syphilis between August 2008 and August 2009 were interviewed. All were MSM and performed anal intercourse, while 13 (55%) reported unprotected anal intercourse. Most participants (21, 91%) practiced unprotected oral intercourse. Nine participants (39%) reported unprotected oral intercourse while using condoms during anal intercourse. Ten participants (43%) reported sexual contacts while traveling abroad in the previous few months. Most participants (96%) were co-infected with HIV, and 15 (68%) were already aware of their HIV infection. Fifteen (66%) reported the use of recreational drugs, alcohol, or both before or during sex. No common source or core transmitters were identified.CONCLUSIONS:This syphilis outbreak included MSM who were co-infected with HIV and were characterized by risky sexual behavior including multiple partners, unprotected anal intercourse and substance use. Future targeted interventions should focus on HIV-infected MSM for secondary prevention.

Cat scratch disease (CSD) is a common cause of subacute infectious regional lymphadenitis, caused by Bartonella henselae. Presently, detection of anti-B. henselae antibodies by immunofluorescence antibody assay or enzyme immunoassay (EIA) is the most widely used diagnostic test for CSD, but both are limited in establishing the timing of infection with B. henselae. In the present work we developed an avidity test for anti-B. henselae immunoglobulin G (IgG) based on EIA to distinguish recent from past CSD. We used 101 serum samples from 79 CSD patients with positive anti-B. henselae IgG as verified by EIA, and systematically developed an avidity assay using various detergent (urea) concentrations and incubation settings to optimize the test conditions to differentiate early CSD (less than 12 weeks) from late CSD (12 weeks or more). After serial experiments, the optimal conditions for performing the avidity test included incubation for 10 min at room temperature with 8 M urea at pH 7.4, and these parameters were used in the study. Our experiments showed that while the avidity indexes (AIs) of the early CSD samples were widely distributed, all the late CSD sera samples had AIs above 43, indicating that an AI <43 can serve as evidence of early CSD. The results of this study indicate that the avidity test can be useful in the serodiagnosis of CSD, particularly when anti-B. henselae IgM antibodies are not detected.

The K65R mutation in HIV‐1 reverse transcriptase (RT) can be selected by the RT inhibitors tenofovir (TDF), abacavir (ABC), and didanosine (DDI). Recently, in vitro studies have shown that K65R is selected in tissue culture more rapidly with subtype C than subtype B viruses. The prevalence of K65R in viruses sequenced at the Tel‐Aviv AIDS Center was evaluated. This study analyzed retrospectively sequences from 1999 to 2007 in patients treated with TDF, ABC, and/or DDI and compared rates of mutational prevalence between subtypes. Fisher's exact test was used to determine statistical significance. Forty‐four sequences from patients treated with the three above‐cited drugs were analyzed. Subtypes A (n = 1), CRF01_AE (n = 4), CRF02_AG (n = 2), B (n = 21), C (n = 11), D (n = 1), F (n = 3), and G (n = 1) were represented. Seven non‐B viruses had the K65R mutation, which was only found in one subtype B virus. Of these seven samples four were subtype C, one was subtype CRF01_AE, and two were subtype CRF02_AG. None of the eight viruses with K65R harbored thymidine analogue mutations. In this study, non‐subtype B viruses possessed the K65R mutation at higher incidence than subtype B viruses. Subtype C viruses may be especially prone to develop this mutation. Larger studies are needed to confirm these data. Efforts should be intensified to understand better differences in drug resistance between various HIV subtypes. J. Med. Virol. 81:1509–1512, 2009. © 2009 Wiley‐Liss, Inc.