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1.
N Engl J Med ; 2021 Oct 06.
Article in English | MEDLINE | ID: mdl-34614328

ABSTRACT

BACKGROUND: Approximately 5.1 million Israelis had been fully immunized against coronavirus disease 2019 (Covid-19) after receiving two doses of the BNT162b2 messenger RNA vaccine (Pfizer-BioNTech) by May 31, 2021. After early reports of myocarditis during adverse events monitoring, the Israeli Ministry of Health initiated active surveillance. METHODS: We retrospectively reviewed data obtained from December 20, 2020, to May 31, 2021, regarding all cases of myocarditis and categorized the information using the Brighton Collaboration definition. We analyzed the occurrence of myocarditis by computing the risk difference for the comparison of the incidence after the first and second vaccine doses (21 days apart); by calculating the standardized incidence ratio of the observed-to-expected incidence within 21 days after the first dose and 30 days after the second dose, independent of certainty of diagnosis; and by calculating the rate ratio 30 days after the second dose as compared with unvaccinated persons. RESULTS: Among 304 persons with symptoms of myocarditis, 21 had received an alternative diagnosis. Of the remaining 283 cases, 142 occurred after receipt of the BNT162b2 vaccine; of these cases, 136 diagnoses were definitive or probable. The clinical presentation was judged to be mild in 129 recipients (95%); one fulminant case was fatal. The overall risk difference between the first and second doses was 1.76 per 100,000 persons (95% confidence interval [CI], 1.33 to 2.19), with the largest difference among male recipients between the ages of 16 and 19 years (difference, 13.73 per 100,000 persons; 95% CI, 8.11 to 19.46). As compared with the expected incidence based on historical data, the standardized incidence ratio was 5.34 (95% CI, 4.48 to 6.40) and was highest after the second dose in male recipients between the ages of 16 and 19 years (13.60; 95% CI, 9.30 to 19.20). The rate ratio 30 days after the second vaccine dose in fully vaccinated recipients, as compared with unvaccinated persons, was 2.35 (95% CI, 1.10 to 5.02); the rate ratio was again highest in male recipients between the ages of 16 and 19 years (8.96; 95% CI, 4.50 to 17.83), with a ratio of 1 in 6637. CONCLUSIONS: The incidence of myocarditis, although low, increased after the receipt of the BNT162b2 vaccine, particularly after the second dose among young male recipients. The clinical presentation of myocarditis after vaccination was usually mild.

3.
Eur J Haematol ; 2021 Sep 26.
Article in English | MEDLINE | ID: mdl-34564876

ABSTRACT

The characteristics of infections following chimeric antigen receptor T (CAR-T) cells targeting CD19 in real-word population are obscure. We analyzed infections' characteristics in the first month among consecutive patients with diffuse large B-cell lymphoma (DLBCL) (n = 60, median age, 69.3 years), treated with commercial CAR-T cells. ECOG performance status (PS) was 2-3 in most patients (58%). Infections were observed in 45% of patients (16, 27%, bacterial infections, and 14, 23%, viral infections). Bacterial infection included clinically documented infection in 7 (Pneumonia, n = 5; periodontal infection, n = 1; and cellulitis, n = 1) and microbiology documented infection (MDI) in 9 patients (Gram-negative rod, n = 5; Gram-positive cocci, n = 3, bacteremia; polymicrobial, n = 1). The most common viral infection was cytomegalovirus (CMV) reactivation (n = 10, 17%) leading to initiation of anti-CMV treatment in 6 (60%) among these patients. None had CMV disease. In univariate analysis, immune effector cell-associated neurotoxicity syndrome (ICANS) was associated with higher incidence of bacterial infection (OR=4.5, P = .018), while there was a trend for lower incidence of bacterial infections in patients with chemosensitive disease to bridging therapy (OR=0.375, P = .074). Age or PS was not associated with increased risk of bacterial infection. Increase in C-reactive protein (CRP) prior to fever onset was associated with microbiologically documented infections. We conclude that infections are common in the first month following CAR-T-cell administration, however, were not increased in elderly patients or those presenting with poorer PS. Increase in CRP prior to fever onset could support infection over cytokine release syndrome.

4.
Infect Control Hosp Epidemiol ; : 1-4, 2021 Sep 20.
Article in English | MEDLINE | ID: mdl-34538284

ABSTRACT

Real-world studies have demonstrated impressive effectiveness of the BNT162b2 COVID-19 vaccine in preventing symptomatic and asymptomatic SARS-CoV-2 infection. We describe an outbreak of SARS-CoV-2 infections in a hospital with high vaccine uptake. We found a low secondary attack rate (7%), suggesting low infectivity of vaccinated persons with vaccine breakthrough SARS-CoV-2 infections.

5.
Emerg Infect Dis ; 27(8): 2117-2126, 2021 08.
Article in English | MEDLINE | ID: mdl-34286684

ABSTRACT

In a multicenter, nationwide, retrospective study of patients hospitalized with spotted fever group rickettsiosis in Israel during 2010-2019, we identified 42 cases, of which 36 were autochthonous. The most prevalent species was the Rickettsia conorii Israeli tick typhus strain (n = 33, 79%); infection with this species necessitated intensive care for 52% of patients and was associated with a 30% fatality rate. A history of tick bite was rare, found for only 5% of patients; eschar was found in 12%; and leukocytosis was more common than leukopenia. Most (72%) patients resided along the Mediterranean shoreline. For 3 patients, a new Rickettsia variant was identified and had been acquired in eastern, mountainous parts of Israel. One patient had prolonged fever before admission and clinical signs resembling tickborne lymphadenopathy. Our findings suggest that a broad range of Rickettsia species cause spotted fever group rickettsiosis in Israel.


Subject(s)
Rickettsia conorii , Rickettsia , Spotted Fever Group Rickettsiosis , Humans , Israel/epidemiology , Retrospective Studies , Rickettsia/genetics , Spotted Fever Group Rickettsiosis/diagnosis , Spotted Fever Group Rickettsiosis/epidemiology
6.
Transplant Cell Ther ; 27(9): 788-794, 2021 09.
Article in English | MEDLINE | ID: mdl-34214738

ABSTRACT

Data are scarce regarding both the safety and immunogenicity of the BNT162b2 mRNA COVID-19 vaccine in patients undergoing immune cell therapy; thus, we prospectively evaluated these two domains in patients receiving this vaccine after allogeneic hematopoietic cell transplantation (HCT; n = 66) or after CD19-based chimeric antigen receptor T cell (CART) therapy (n = 14). Overall, the vaccine was well tolerated, with mild non-hematologic vaccine-reported adverse events in a minority of the patients. Twelve percent of the patients after the first dose and 10% of the patients after the second dose developed cytopenia, and there were three cases of graft-versus-host disease exacerbation after each dose. A single case of impending graft rejection was summarized as possibly related. Evaluation of immunogenicity showed that 57% of patients after CART infusion and 75% patients after allogeneic HCT had evidence of humoral and/or cellular response to the vaccine. The Cox regression model indicated that longer time from infusion of cells, female sex, and higher CD19+ cells were associated with a positive humoral response, whereas a higher CD4+/CD8+ ratio was correlated with a positive cellular response, as confirmed by the ELISpot test. We conclude that the BNT162b2 mRNA COVID-19 vaccine has impressive immunogenicity in patients after allogeneic HCT or CART. Adverse events were mostly mild and transient, but some significant hematologic events were observed; hence, patients should be closely monitored.


Subject(s)
COVID-19 , Hematopoietic Stem Cell Transplantation , COVID-19 Vaccines , Female , Humans , Prospective Studies , RNA, Messenger/genetics , SARS-CoV-2
7.
Antimicrob Agents Chemother ; 65(10): e0108921, 2021 09 17.
Article in English | MEDLINE | ID: mdl-34280014

ABSTRACT

Triazole resistance in the pathogenic mold Aspergillus fumigatus has increased worldwide, posing a growing therapeutic challenge. Recently, mutations in the 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase gene (hmg1) have been associated with triazole resistance. Here, we describe a novel E306K triazole resistance-conferring mutation in the HMG-CoA reductase gene from an Israeli patient with chronic cavitary pulmonary aspergillosis (CCPA).


Subject(s)
HMGB1 Protein , Pulmonary Aspergillosis , Antifungal Agents/pharmacology , Antifungal Agents/therapeutic use , Aspergillus fumigatus/genetics , Drug Resistance, Fungal/genetics , Fungal Proteins/genetics , Humans , Pulmonary Aspergillosis/drug therapy , Triazoles/pharmacology
8.
Antimicrob Agents Chemother ; 65(10): e0125221, 2021 09 17.
Article in English | MEDLINE | ID: mdl-34310208

ABSTRACT

Aspergillus fumigatus is the most common cause of invasive fungal mold infections in immunocompromised individuals. Current antifungal treatment relies heavily on the triazole antifungals which inhibit fungal Erg11/Cyp51 activity and subsequent ergosterol biosynthesis. However, resistance, due primarily to cyp51 mutation, is rapidly increasing. A. fumigatus contains two Cyp51 isoenzymes, Cyp51A and Cyp51B. Overexpression and mutation of Cyp51A is a major cause of triazole resistance in A. fumigatus. The role of Cyp51B in generating resistance is unclear. Here, we show that overexpression or mutation of cyp51B results in triazole resistance. We demonstrate that introduction of a G457S Cyp51B mutation identified in a resistant clinical isolate results in voriconazole resistance in a naive recipient strain. Our results indicate that mutations in cyp51B resulting in clinical resistance do exist and should be monitored.


Subject(s)
Aspergillus fumigatus , Lanosterol , Antifungal Agents/pharmacology , Aspergillus fumigatus/genetics , Cytochrome P-450 Enzyme System/genetics , Drug Resistance, Fungal/genetics , Fungal Proteins/genetics , Humans , Mutation , Point Mutation , Sterols , Triazoles/pharmacology
9.
J Antimicrob Chemother ; 76(9): 2415-2418, 2021 08 12.
Article in English | MEDLINE | ID: mdl-34075419

ABSTRACT

OBJECTIVES: To assess whether results of observational studies of potential anti-COVID-19 drugs were reproduced in subsequent randomized controlled trials (RCTs). METHODS: This was a retrospective cross-sectional study, including studies published online between 1 January and 27 October 2020 that evaluated potential COVID-19 treatments and reported all-cause mortality. RESULTS: Of 133 comparisons included in 117 studies, most were non-randomized (104/133, 78%). Hydroxychloroquine was the most common drug type, combined with azithromycin (n = 27, 20%) or alone (n = 22, 16%), followed by IL-6 inhibitors (n = 36, 27%) and corticosteroids (n = 26, 20%). Seventy-one percent (74/104) of non-randomized studies reported adjusted survival results and only 8% (8/104) adjusted for immortal time bias. Only two RCTs (2/29, 7%) reported significant survival benefit, both reporting treatment with corticosteroids, while 32/104 (31%) non-randomized studies showed statistically significant survival benefit associated with the intervention arm. The results of the majority (28/32, 88%) of non-randomized studies reporting survival benefit were not replicated by large-scale RCTs. CONCLUSIONS: The results of most non-randomized studies reporting survival benefit of potential anti-COVID-19 drugs were not replicated by large RCTs. Regulators and healthcare professionals should exercise caution and resist the pressure to approve and prescribe drugs of unproven efficacy and potential toxicity to optimize patient care and maintain public trust in medical science.


Subject(s)
COVID-19 , Pharmaceutical Preparations , Cross-Sectional Studies , Humans , Hydroxychloroquine , Retrospective Studies , SARS-CoV-2
10.
JAMA ; 325(24): 2457-2465, 2021 Jun 22.
Article in English | MEDLINE | ID: mdl-33956048

ABSTRACT

Importance: Randomized clinical trials have provided estimates of the effectiveness of the BNT162b2 vaccine against symptomatic SARS-CoV-2 infection, but its effect on asymptomatic infections remains unclear. Objective: To estimate the association of vaccination with the Pfizer-BioNTech BNT162b2 vaccine with symptomatic and asymptomatic SARS-CoV-2 infections among health care workers. Design, Setting, and Participants: This was a single-center, retrospective cohort study conducted at a tertiary medical center in Tel Aviv, Israel. Data were collected on symptomatic and asymptomatic SARS-CoV-2 infections confirmed via polymerase chain reaction (PCR) tests in health care workers undergoing regular screening with nasopharyngeal swabs between December 20, 2020, and February 25, 2021. Logistic regression was used to calculate incidence rate ratios (IRRs) comparing the incidence of infection between fully vaccinated and unvaccinated participants, controlling for demographics and the number of PCR tests performed. Exposures: Vaccination with the BNT162b2 vaccine vs unvaccinated status was ascertained from the employee health database. Full vaccination was defined as more than 7 days after receipt of the second vaccine dose. Main Outcomes and Measures: The primary outcome was the regression-adjusted IRR for symptomatic and asymptomatic SARS-CoV-2 infection of fully vaccinated vs unvaccinated health care workers. The secondary outcomes included IRRs for partially vaccinated health care workers (days 7-28 after first dose) and for those considered as late fully vaccinated (>21 days after second dose). Results: A total of 6710 health care workers (mean [SD] age, 44.3 [12.5] years; 4465 [66.5%] women) were followed up for a median period of 63 days; 5953 health care workers (88.7%) received at least 1 dose of the BNT162b2 vaccine, 5517 (82.2%) received 2 doses, and 757 (11.3%) were not vaccinated. Vaccination was associated with older age compared with those who were not vaccinated (mean age, 44.8 vs 40.7 years, respectively) and male sex (31.4% vs 17.7%). Symptomatic SARS-CoV-2 infection occurred in 8 fully vaccinated health care workers and 38 unvaccinated health care workers (incidence rate, 4.7 vs 149.8 per 100 000 person-days, respectively, adjusted IRR, 0.03 [95% CI, 0.01-0.06]). Asymptomatic SARS-CoV-2 infection occurred in 19 fully vaccinated health care workers and 17 unvaccinated health care workers (incidence rate, 11.3 vs 67.0 per 100 000 person-days, respectively, adjusted IRR, 0.14 [95% CI, 0.07-0.31]). The results were qualitatively unchanged by the propensity score sensitivity analysis. Conclusions and Relevance: Among health care workers at a single center in Tel Aviv, Israel, receipt of the BNT162b2 vaccine compared with no vaccine was associated with a significantly lower incidence of symptomatic and asymptomatic SARS-CoV-2 infection more than 7 days after the second dose. Findings are limited by the observational design.


Subject(s)
COVID-19 Vaccines , COVID-19/epidemiology , Health Personnel , Adult , Asymptomatic Infections/epidemiology , COVID-19/diagnosis , COVID-19/prevention & control , Female , Humans , Incidence , Israel , Male , Middle Aged , Polymerase Chain Reaction , Propensity Score , Retrospective Studies , SARS-CoV-2/isolation & purification , Tertiary Care Centers
11.
Infect Dis Clin North Am ; 35(2): 279-311, 2021 06.
Article in English | MEDLINE | ID: mdl-34016279

ABSTRACT

Pathogenic fungi have several mechanisms of resistance to antifungal drugs, driven by the genetic plasticity and versatility of their homeostatic responses to stressful environmental cues. We critically review the molecular mechanisms of resistance and cellular adaptations of pathogenic fungi in response to antifungals and discuss the factors contributing to such resistance. We offer suggestions for the translational and clinical research agenda of this rapidly evolving and medically important field. A better understanding of antifungal resistance should assist in developing better detection tools and inform optimal strategies for preventing and treating refractory mycoses in the future.

12.
Isr Med Assoc J ; 23(5): 312-317, 2021 May.
Article in English | MEDLINE | ID: mdl-34024049

ABSTRACT

BACKGROUND: Pneumocystis jirovecii pneumonia (PJP) is an opportunistic infection in immunocompromised patients. Clusters of PJP, especially among organ transplant recipients in clinic settings were described. Data regarding nosocomial PJP infection among inpatients are limited. OBJECTIVES: To assess the magnitude and characteristics of inpatient healthcare-associated PJP infection (HCA-PJP) in HIV-negative patients. METHODS: A retrospective chart review of hospitalized PJP patients was performed to identify HCA-PJP. The study was performed at six medical centers in Israel from 2006 to 2016. HCA-PJP was defined as cases of hospital-onset or those with documented contact with a PJP patient. We reviewed and cross-matched temporal and spatial co-locations of patients. Clinical laboratory characteristics and outcomes were compared. RESULTS: Seventy-six cases of PJP were identified. Median age was 63.7 years; 64% men; 44% hematological malignancies; 18% inflammatory diseases; and 61% steroid usage. Thirty-two patients (42%) were defined as HCA-PJP: 18/32 (23.6%) were hospitalized at onset and 14/32 (18.4%) had a previous encounter with a PJP patient. Time from onset of symptoms to diagnosis was shorter in HCA-PJP vs. community-PJP (3.25 vs. 11.23 days, P = 0.009). In multivariate analysis, dyspnea at presentation (odds ratio [OR] 16.79, 95% confidence interval [95%CI] 1.78-157.95) and a tendency toward higher rate of ventilator support (72% vs. 52%, P = 0.07, OR 5.18, 95%CI 0.7-30.3) were independently associated with HCA-PJP, implying abrupt disease progression in HCA-PJP. CONCLUSIONS: HCA-PJP was common. A high level of suspicion for PJP among selected patients with nosocomial respiratory infection is warranted. Isolation of PJP patients should be considered.


Subject(s)
Cross Infection/epidemiology , Opportunistic Infections/epidemiology , Pneumocystis carinii/isolation & purification , Pneumonia, Pneumocystis/epidemiology , Aged , Cross Infection/diagnosis , Cross Infection/microbiology , Disease Progression , Dyspnea/etiology , Female , Hospitals , Humans , Israel , Male , Middle Aged , Opportunistic Infections/diagnosis , Opportunistic Infections/microbiology , Pneumonia, Pneumocystis/diagnosis , Pneumonia, Pneumocystis/microbiology , Respiration, Artificial/statistics & numerical data , Retrospective Studies , Time Factors
13.
Life (Basel) ; 11(3)2021 Mar 20.
Article in English | MEDLINE | ID: mdl-33804790

ABSTRACT

BACKGROUND: The human anti-IL-6 receptor antibody tocilizumab (TCZ) has been approved for the treatment of rheumatoid arthritis (RA) and giant cell arteritis (GCA). It is observed that CRP levels drop quickly after starting TCZ treatment. This may lead to misinterpretation of laboratory results when accessing the patient with infectious disease while on TCZ. We conducted this study to report cases treated with tocilizumab who developed serious infections with special reference to levels of CRP and to review the literature on the effect of tocilizumab on acute phase response (APR) during infections. METHODS: The files of RA and GCA patients hospitalized in the Tel Aviv medical center between 2009-2019 were reviewed. Cases of patients with RA and GCA treated with tocilizumab who were hospitalized due to severe infections were reviewed with special emphasis on the duration of treatment, type of infection, and APR. RESULTS: We identified nine admissions. Seven patients were treated with tocilizumab for RA, two for GCA. The diagnosis was pneumonia in three cases, osteomyelitis in one, cellulitis in one, endocarditis due to Whipple disease in one, abscess of cervix uteri in one, meningitis in one, and perforated diverticulitis in one. The mean CRP levels on admission were 4.75 mg/L (normal range, up to 5 mg/L). All cases were diagnosed correctly on admission. CONCLUSIONS: CRP levels may not correctly reflect the severity of infectious diseases during tocilizumab treatment. Increased awareness of the masking effect of tocilizumab on the APR during infection is needed in order to avoid a delay in the diagnosis.

14.
Lancet ; 397(10273): 499-509, 2021 02 06.
Article in English | MEDLINE | ID: mdl-33549194

ABSTRACT

BACKGROUND: Voriconazole has been recommended as primary treatment for patients with invasive aspergillosis. Intravenous and tablet formulations of posaconazole that have improved systemic absorption could be an effective alternative to voriconazole. We aimed to assess non-inferiority of posaconazole to voriconazole for the primary treatment of invasive aspergillosis. METHODS: We did a randomised, prospective, double-blind, double-dummy, controlled trial comparing posaconazole (intravenous or oral posaconazole 300 mg twice on day 1, followed by 300 mg once a day for days 2-84) with voriconazole (6 mg/kg intravenous or 300 mg oral twice on day 1 followed by 4 mg/kg intravenously or 200 mg orally twice a day for days 2-84) for 12 weeks or less in the primary treatment of invasive aspergillosis. Participants were from 91 study sites in 26 countries, were aged 13 years or older, weighed at least 40 kg, and met criteria for proven, probable, or possible fungal disease. Participants were randomly assigned (1:1) via a computer-generated randomisation schedule with stratification by risk status. The primary endpoint was cumulative all-cause mortality up until day 42 in the intention-to-treat (ITT) population (defined as randomly assigned participants who received ≥1 dose of study drug), with a 10% non-inferiority margin. The ITT population was also evaluated for safety. This study is registered with ClinicalTrials.gov, NCT01782131, and EudraCT, 2011-003938-14. FINDINGS: Between Oct 25, 2013, and Sept 10, 2019, of 653 individuals assessed for eligibility, 575 ITT participants were randomly assigned and received one or more doses of study drug (n=288 [50%] posaconazole, n=287 [50%] voriconazole). Mortality up until day 42 was 15% (44 of 288) in the posaconazole group and 21% (59 of 287) in the voriconazole group (treatment difference -5·3% [95% CI -11·6 to 1·0]; p<0·0001). Mortality up until day 42 in the full-analysis-set subpopulation (ITT participants with proven or probable invasive aspergillosis) supported this conclusion: 31 (19%) of 163 participants in the posaconazole group and 32 (19%) of 171 participants in the voriconazole group (treatment difference 0·3% [95% CI -8·2 to 8·8]). The most frequently reported treatment-related adverse events (incidence >3%) were increased aspartate aminotransferase (AST) or alanine aminotransferase (ALT), nausea, hypokalaemia, and vomiting in the posaconazole group and increased ALT, AST, or alkaline phosphatase, hallucination, increased γ-glutamyltransferase peptidase, nausea, and blurred vision in the voriconazole group. The overall incidence of treatment-related adverse event rates in the ITT population was 30% for posaconazole and 40% for voriconazole (treatment difference -10·2% [95% CI -17·9 to -2·4]). INTERPRETATION: Posaconazole was non-inferior to voriconazole for all-cause mortality up until day 42 in participants with invasive aspergillosis. Posaconazole was well tolerated, and participants had fewer treatment-related adverse events than in the voriconazole group. This study supports the use of posaconazole as a first-line treatment for the condition. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co, Inc.


Subject(s)
Antifungal Agents/administration & dosage , Invasive Pulmonary Aspergillosis/drug therapy , Triazoles/administration & dosage , Voriconazole/administration & dosage , Administration, Intravenous , Administration, Oral , Adolescent , Adult , Antifungal Agents/adverse effects , Double-Blind Method , Female , Humans , Invasive Pulmonary Aspergillosis/mortality , Male , Middle Aged , Prospective Studies , Triazoles/adverse effects , Voriconazole/adverse effects , Young Adult
15.
BMJ Open ; 11(2): e040210, 2021 02 08.
Article in English | MEDLINE | ID: mdl-33558347

ABSTRACT

INTRODUCTION: The optimal treatment for extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae bloodstream infections has yet to be defined. Retrospective studies have shown conflicting results, with most data suggesting the non-inferiority of beta-lactam-beta-lactamase inhibitor combinations compared with carbapenems. However, the recently published MERINO trial failed to demonstrate the non-inferiority of piperacillin-tazobactam to meropenem. The potential implications of the MERINO trial are profound, as widespread adoption of carbapenem treatment will have detrimental effects on antimicrobial stewardship in areas endemic for ESBL and carbapenem-resistant bacteria. Therefore, we believe that it is justified to re-examine the comparison in a second randomised controlled trial prior to changing clinical practice. METHODS AND ANALYSIS: PeterPen is a multicentre, investigator-initiated, open-label, randomised controlled non-inferiority trial, comparing piperacillin-tazobactam with meropenem for third-generation cephalosporin-resistant Escherichia coli and Klebsiella bloodstream infections. The study is currently being conducted in six centres in Israel and one in Canada with other centres from Israel, Italy and Canada expected to join. The two primary outcomes are all-cause mortality at day 30 from enrolment and treatment failure at day seven (death, fever above 38°C in the last 48 hours, continuous symptoms, increasing Sequential Organ Failure Assessment Score or persistent blood cultures with the index pathogen). A sample size of 1084 patients was calculated for the mortality endpoint assuming a 12.5% mortality rate in the control group with a 5% non-inferiority margin and assuming 100% follow-up for this outcome. ETHICS AND DISSEMINATION: The study is approved by local and national ethics committees as required. Results will be published, and trial data will be made available. TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov Registry (NCT03671967); Israeli Ministry of Health Trials Registry (MOH_2018-12-25_004857).


Subject(s)
Enterobacteriaceae , Sepsis , Anti-Bacterial Agents/therapeutic use , Canada , Cephalosporins , Humans , Israel , Italy , Meropenem/therapeutic use , Multicenter Studies as Topic , Randomized Controlled Trials as Topic , Retrospective Studies , Sepsis/drug therapy , beta-Lactamases
16.
Mycoses ; 64(1): 78-85, 2021 Jan.
Article in English | MEDLINE | ID: mdl-33000505

ABSTRACT

BACKGROUND: Treatment of Candida albicans bloodstream infection with fluconazole is associated with significant mortality despite in vitro susceptibility to the drug. OBJECTIVES: We sought to determine whether tolerance to fluconazole is predictive of treatment failure. METHODS: We reviewed patients with monomicrobial C albicans bloodstream infection who received primary monotherapy with fluconazole. Tolerance to fluconazole, defined as the fraction of growth above the MIC, was quantified using the disc diffusion assay and digital image analyses. Survival analyses were performed with host and treatment factors as predictive variables. RESULTS: Among 44 patients included in the study, all-cause mortality was 29.5% at 30 days and 43.1% at 12 weeks. Forty-one isolates (93%) were susceptible to fluconazole (MIC50, 0.5 mg/L). Fluconazole tolerance was strongly associated with death for patients treated with fluconazole within 24 h of candidemia onset (33.3% vs 0%; p = .007), but not among patients whose treatment was started later. MIC did not correlate with survival, regardless of treatment delay. A Cox regression model including time to treatment, tolerance to fluconazole, fluconazole exposure and Pitt bacteraemia score provided good prediction of treatment outcome (area under the receiver-operator curve, 0.82). CONCLUSIONS: In patients with C albicans bloodstream infection, tolerance testing was predictive of fluconazole efficacy if the drug was started early. Further study is required to validate the utility of this metric to guide treatment choices.


Subject(s)
Antifungal Agents/therapeutic use , Candidemia/drug therapy , Candidiasis/drug therapy , Fluconazole/therapeutic use , Adult , Aged , Aged, 80 and over , Candida albicans , Candidiasis/mortality , Cohort Studies , Drug Resistance, Fungal , Female , Humans , Male , Microbial Sensitivity Tests , Middle Aged , Survival Analysis , Treatment Failure , Treatment Outcome
18.
PLoS One ; 15(9): e0239042, 2020.
Article in English | MEDLINE | ID: mdl-32915907

ABSTRACT

OBJECTIVE: Pneumocystis jirovecii pneumonia (PJP) was reported among immunosuppressed patients with deficits in cell-mediated immunity and in patients treated with immunomodulatory drugs. The aim of this study was to identify risk-factors for PJP in noninfected HIV patients. METHODS: This retrospective, test negative, case-control study was conducted in six hospitals in Israel, 2006-2016. Cases were hospitalized HIV-negative patients with pneumonia diagnosed as PJP by bronchoalveolar lavage. Controls were similar patients negative for PJP. RESULTS: Seventy-six cases and 159 controls were identified. Median age was 63.7 years, 65% males, 34% had hematological malignancies, 11% inflammatory diseases, 47% used steroids and 9% received antilymphocyte monoclonal antibodies. PJP was independently associated with antilymphocyte monoclonal antibodies (OR 11.47, CI 1.50-87.74), high-dose steroid treatment (OR 4.39, CI 1.52-12.63), lymphopenia (OR 8.13, CI 2.48-26.60), low albumin (OR 0.15, CI 0.40-0.54) and low BMI (OR 0.80, CI 0.68-0.93). CONCLUSION: In conclusion, rituximab, which is prescribed for a wide variety of malignant and inflammatory disorders, was found to be significant risk-factor for PJP. Increased awareness of possible PJP infection in this patient population is warranted.


Subject(s)
Pneumocystis carinii , Pneumonia, Pneumocystis/etiology , Rituximab/adverse effects , Adult , Aged , Aged, 80 and over , Antilymphocyte Serum/adverse effects , Antineoplastic Agents, Immunological/adverse effects , Case-Control Studies , Female , HIV Seronegativity , Hematologic Neoplasms/complications , Hematologic Neoplasms/drug therapy , Hematologic Neoplasms/immunology , Humans , Immunologic Factors/adverse effects , Israel , Male , Middle Aged , Multivariate Analysis , Retrospective Studies , Risk Factors , Steroids/adverse effects
19.
Mycoses ; 63(10): 1060-1068, 2020 Oct.
Article in English | MEDLINE | ID: mdl-32485012

ABSTRACT

BACKGROUND: Regional differences in the underlying causes, manifestations and treatment of mucormycosis have been noted in studies covering Europe, Asia and South America. OBJECTIVES: To review cases of mucormycosis across the Middle East and North Africa (MENA) region in order to identify epidemiological, treatment and outcome trends in this region. PATIENTS/METHODS: Cases of proven or probable invasive mucormycosis from the region were identified from the FungiScope® database and the medical literature. For each case, information on underlying condition, site of infection, pathogenic species, therapeutic intervention, type of antifungal therapy and outcome were analysed. RESULTS: We identified 310 cases of mucormycosis in the MENA region. The number of reported cases increased by decade from 23 before 1990 to 127 in the 2010s. In this region, the most common underlying conditions associated with mucormycosis were diabetes mellitus (49.7%) and conditions associated with immunosuppression (46.5%). The majority of patients received treatment with antifungals (93.5%), with a large proportion treated with both antifungals and surgery (70.6%). Overall mortality rates decreased from 47.8% before 1990 to 32.3% in the 2010s. CONCLUSIONS: The number of reported cases of mucormycosis in the MENA region has risen over the past few decades, in line with increases in the number of patients with underlying conditions associated with this infection. Although the majority of patients received treatment with antifungal therapies and/or surgery, the associated mortality rate remains high and there is a clear need for more effective prevention and treatment strategies in the MENA region.


Subject(s)
Mucormycosis , Africa, Northern/epidemiology , Antifungal Agents/therapeutic use , Diabetes Complications , Humans , Immunosuppression , Middle East/epidemiology , Mortality , Mucormycosis/drug therapy , Mucormycosis/epidemiology , Mucormycosis/pathology , Mucormycosis/surgery , Registries , Risk Factors
20.
Front Genet ; 11: 554, 2020.
Article in English | MEDLINE | ID: mdl-32587603

ABSTRACT

The recent emergence of a multidrug-resistant yeast, Candida auris, has drawn attention to the closely related species from the Candida haemulonii complex that include C. haemulonii, Candida duobushaemulonii, Candida pseudohaemulonii, and the recently identified Candida vulturna. Here, we used antifungal susceptibility testing and whole-genome sequencing (WGS) to investigate drug resistance and genetic diversity among isolates of C. haemulonii complex from different geographic areas in order to assess population structure and the extent of clonality among strains. Although most isolates of all four species were genetically distinct, we detected evidence of the in-hospital transmission of C. haemulonii and C. duobushaemulonii in one hospital in Panama, indicating that these species are also capable of causing outbreaks in healthcare settings. We also detected evidence of the rising azole resistance among isolates of C. haemulonii and C. duobushaemulonii in Colombia, Panama, and Venezuela linked to substitutions in ERG11 gene as well as amplification of this gene in C. haemulonii in isolates in Colombia suggesting the presence of evolutionary pressure for developing azole resistance in this region. Our results demonstrate that these species need to be monitored as possible causes of outbreaks of invasive infection.

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