Mical Paul

Technion - Israel Institute of Technology, H̱efa, Haifa, Israel

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Publications (177)1112.89 Total impact

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    ABSTRACT: Carbapenem-resistant Gram-negative bacteria (CRGNB) pose a clinical challenge. We attempted to estimate the mortality burden of CRGNB among haematological cancer patients. This was a retrospective cohort study. We included adult patients hospitalized in the haemato-oncological/bone marrow transplantation departments for chemotherapy, between 2008 and 2014, with Gram-negative aerobic bacteraemia. We compared patients with CRGNB and carbapenem-susceptible Gram-negative bacteraemia (CSGNB). The primary outcome was 14 day all-cause mortality. In addition, we assessed 1 year survival. Multivariable logistics regression analysis and adjusted Cox regression analysis were conducted. Analyses were adjusted to the propensity for CRGNB bacteraemia. The cohort included mostly young patients (mean age 50.1 years) with acute leukaemia (264/423, 62.4%) and the median absolute neutrophil count at bacteraemia onset was 0 × 10(9)/L. The unadjusted 14 day mortality rate was higher for patients with CRGNB compared with CSGNB [45.6% (47/103) versus 15% (48/320), respectively (P < 0.001)]. Adjusting to baseline prognostic factors, infection characteristics and the propensity score retained a significant association between CRGNB and 14 day mortality (OR 5.14, 95% CI 2.32-11.38). Including only the first bacteraemic episode per patient, 1 year mortality was 74.7% (68/91) for patients with CRGNB versus 49.8% (119/239) for patients with CSGNB (P < 0.001). Adjusting for risk factors associated with 1 year mortality, the HR for mortality with CRGNB was 1.48 (95% CI 1-2.2). CRGNB bacteraemia was associated with several risk factors for mortality, including inappropriate empirical antibiotic treatment and less effective definitive antibiotics. This study demonstrated a significant adjusted association between CRGNB and mortality up to 1 year among haemato-oncological patients receiving chemotherapy. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
    Journal of Antimicrobial Chemotherapy 07/2015; DOI:10.1093/jac/dkv218 · 5.44 Impact Factor
  • Ursula Theuretzbacher · Mical Paul
    Clinical Microbiology and Infection 06/2015; DOI:10.1016/j.cmi.2015.06.019 · 5.20 Impact Factor
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    ABSTRACT: In the face of increasing antimicrobial resistance and the paucity of new antimicrobial agents it has become clear that new antimicrobial strategies are urgently needed. One of these is to revisit old antibiotics to ensure that they are used correctly and to their full potential, as well as to determine whether one or several of them can help alleviate the pressure on more recent agents. Strategies are urgently needed to 're-develop' these drugs using modern standards, integrating new knowledge into regulatory frameworks and communicating the knowledge from the research bench to the bedside. Without a systematic approach to re-developing these old drugs and rigorously testing them according to today's standards, there is a significant risk of doing harm to patients and further increasing multidrug resistance. This paper describes factors to be considered and outlines steps and actions needed to re-develop old antibiotics so that they can be used effectively for the treatment of infections. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
    Journal of Antimicrobial Chemotherapy 06/2015; 70(8). DOI:10.1093/jac/dkv157 · 5.44 Impact Factor
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    ABSTRACT: To show non-inferiority of trimethoprim-sulfamethoxazole compared with vancomycin for the treatment of severe infections due to meticillin resistant Staphylococcus aureus (MRSA). Parallel, open label, randomised controlled trial. Four acute care hospitals in Israel. Adults with severe infections caused by MRSA susceptible to trimethoprim-sulfamethoxazole and vancomycin. Patients with left sided endocarditis, meningitis, chronic haemodialysis, and prolonged neutropenia were excluded. Trimethoprim-sulfamethoxazole 320 mg/1600 mg twice daily versus vancomycin 1 g twice daily for a minimum of seven days and then by indication. The primary efficacy outcome was treatment failure assessed at day 7, consisting of death, persistence of haemodynamic instability or fever, stable or worsening Sequential Organ Failure Assessment score, and persistence of bacteraemia. The primary safety outcome was all cause mortality at day 30. Non-inferiority was defined by a difference of less than 15% for treatment failure. 252 patients were included in the trial, of whom 91 (36%) had bacteraemia. No significant difference in treatment failure was seen for trimethoprim-sulfamethoxazole (51/135, 38%) versus vancomycin (32/117, 27%)-risk ratio 1.38 (95% confidence interval 0.96 to 1.99). However, trimethoprim-sulfamethoxazole did not meet the non-inferiority criterion-absolute difference 10.4% (95% confidence interval -1.2% to 21.5%). For patients with bacteraemia, the risk ratio was 1.40 (0.91 to 2.16). In a multivariable logistic regression analysis, trimethoprim-sulfamethoxazole was significantly associated with treatment failure (adjusted odds ratio 2.00, 1.09 to 3.65). The 30 day mortality rate was 32/252 (13%), with no significant difference between arms. Among patients with bacteraemia, 14/41 (34%) treated with trimethoprim-sulfamethoxazole and 9/50 (18%) with vancomycin died (risk ratio 1.90, 0.92 to 3.93). High dose trimethoprim-sulfamethoxazole did not achieve non-inferiority to vancomycin in the treatment of severe MRSA infections. The difference was particularly marked for patients with bacteraemia.Trial registration Clinical trials NCT00427076. © Paul et al 2015.
    BMJ (online) 05/2015; 350(may14 24):h2219. DOI:10.1136/bmj.h2219 · 16.38 Impact Factor
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    ABSTRACT: Traditional wisdom suggests that infections in older patients have atypical presentation, including blunted febrile response. Data are scarce. We analyzed data from a prospectively collected database on presentation of infection in 4,308 patients, and compared the presentation of older patients (≥ 75 years) versus adults (< 75 years). Single tertiary medical center. Patients admitted with suspected bacterial infection during 2002-2004 and 2010-2011. We evaluated clinical presentation on day of admission, including vital signs and laboratory parameters. No difference in fever values as a presenting sign of infection was found between older patients and adults (median fever 38.3°C, interquartile range [IQR] 37.4-39.0°C; and 38.4°C, IQR 37.3-39.0°C, respectively, P = 0.08). Median leukocyte count was significantly higher in older patients (median 11.60, IQR 8.30-15.72 in older patients; 10.84, 7.50-15.00 in adults, P < 0.001). Presentation with septic shock, acute renal failure, and reduced consciousness was significantly more common in older patients. These findings were also consistent in the subgroups of bacteremic patients and patients with microbiologically documented infection. Elevated fever and leukocytosis were found to be at least equally common in older patients compared to younger adults as part of the presentation of infection.
    Annals of Medicine 04/2015; 47(4):1-5. DOI:10.3109/07853890.2015.1019915 · 4.73 Impact Factor
  • Mical Paul · Gilbert Greub
    Clinical Microbiology and Infection 03/2015; 21(4). DOI:10.1016/j.cmi.2015.02.022 · 5.20 Impact Factor
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    ABSTRACT: Objectives To examine how relevant current evidence on antibiotic treatment of pneumonia is for elderly adults.DesignSystematic review.SettingRandomized controlled trials (RCTs; N = 43) comparing different antibiotics and prospective observational studies (N = 182) published since 2005.ParticipantsAdults with community-acquired (CAP), healthcare-associated (HCAP), hospital-acquired (HAP), or ventilator-associated (VAP) pneumonia.MeasurementsExclusion criteria that could preferentially limit participation of elderly adults were examined, subgroup or other adjusted analyses were searched for according to age, and treatment effects in participants younger than 65 in RCTs were compared with those in participants aged 65 and older. Mean participant ages in RCTs and observational studies were compared. Risk ratios (RRs) with 95% confidence intervals (CIs) for differences between older and younger adults were pooled using a fixed effect metaanalysis.ResultsNo RCT reported exclusion based on an upper age limit; 100% of community CAP trials, 90% of hospitalized CAP trials, and 76% of HAP and VAP trials excluded individuals based on comorbidities. None of the RCTs reported a subgroup analysis for mortality according to age. The RR for the pooled difference in treatment failure rates between participants younger than 65 and those aged 65 and older was 1.25 (95% CI = 0.94–1.65, 12 RCTs) and between participants younger than 75 and aged 75 and older was 1.43 (95% CI = 0.98–2.09, 7 RCTs). RCT participants were significantly younger (54.0 ± 9.6) than those in observational studies of CAP (66.2 ± 8.1, P < .001). Age differences were not significant for HCAP, HAP, and VAP.Conclusion Elderly adults are often excluded from RCTs of bacterial pneumonia. No data were found on the comparative efficacy of antibiotic treatment in elderly adults and the general population.
    Journal of the American Geriatrics Society 02/2015; 63(2). DOI:10.1111/jgs.13250 · 4.22 Impact Factor
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    ABSTRACT: Chloramphenicol is an old broad-spectrum antibiotic. We assessed its efficacy and safety. This was a systematic review and meta-analysis. Electronic databases were searched to identify randomized controlled trials (RCTs) that assessed patients, of any age, with systemic bacterial infections that can cause sepsis and compared chloramphenicol alone versus other antibiotics. No restrictions on the date of publication, language or publication status were applied. The primary outcome assessed was overall mortality. Sixty-six RCTs fulfilled the inclusion criteria, and these included 9711 patients. We found a higher mortality with chloramphenicol for respiratory tract infections [risk ratio (RR) 1.40, 95% CI 1.00-1.97] and meningitis (RR 1.27, 95% CI 1.00-1.60), both without heterogeneity. The point estimate was similar for enteric fever, without statistical significance. No statistically significant difference was found between chloramphenicol and other antibiotics regarding treatment failure, except for enteric fever (RR 1.46, 95% CI 1.07-2.00, without heterogeneity). This difference derived mainly from studies comparing chloramphenicol with fluoroquinolones (RR 1.85, 95% CI 1.07-3.2). There were no statistically significant differences between chloramphenicol and other antibiotics in terms of adverse events, including haematological events, except for anaemia, which occurred more frequently with chloramphenicol (RR 2.80, 95% CI 1.65-4.75, I(2) = 0%), and gastrointestinal side effects, which were less frequent with chloramphenicol (RR 0.67, 95% CI 0.46-0.99, I(2) = 0%). Many of the studies included were sponsored by pharmaceutical companies marketing the comparator drug to chloramphenicol, and this might have influenced the results. Chloramphenicol cannot be recommended as a first-line treatment for respiratory tract infections, meningitis or enteric fever as alternatives are probably more effective. Chloramphenicol is as safe as treatment alternatives for short antibiotic courses. RCTs are needed to test this treatment against MDR organisms when better alternatives do not exist. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
    Journal of Antimicrobial Chemotherapy 01/2015; DOI:10.1093/jac/dku530 · 5.44 Impact Factor
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    ABSTRACT: Background: Timing of central venous catheter (CVC) insertion among patients with acute leukemia is debatable. Early insertion increases convenience, but might increase infection rates. Methods: We assessed retrospectively the rate of central line-associated bloodstream infections (CLABSI) according to CVC time of insertion in patients with acute leukemia admitted for induction or salvage therapy. The study was conducted in the Hematology Department of a Tertiary hospital in Israel between 2007 and 2011. Early CVC placement was defined as CVC inserted during the first week of induction therapy. CLABSI rate was documented between the seventh day of induction therapy to 30 days after its completion. Results: A total of 127 patients were included. Acute myeloid leukemia was the most common diagnosis (103 patients, 80.5%). Late CVC placement was associated with CLABSI after adjustment to the Charlson comorbidity index (OR 3.4,95% CI 1.1-10.45), p = 0.03. Conclusion: Delaying CVC placement in adult patients with acute leukemia may be associated with higher rate of CLABSI in the early period after induction therapy.
    Leukemia Research 01/2015; 39(3). DOI:10.1016/j.leukres.2014.12.017 · 2.69 Impact Factor
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    International Journal of Epidemiology 11/2014; 43(6). DOI:10.1093/ije/dyu219 · 9.20 Impact Factor
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    ABSTRACT: Adherence to scheduled chemotherapy is important for optimal outcomes of cancer patients. We examined causes for delay or cancellation of planned chemotherapy, focusing on mild respiratory infections during the winter. Prospective cohort study. We included all adults with solid or hematologic cancer receiving active chemotherapy treatment during the winter of 2010-2011 in a cancer center. We compared baseline characteristics and outcomes between patients with and without chemotherapy delays, cancellations, or dose-reductions ("chemotherapy delay"). We included 547 patients receiving chemotherapy during the winter of 2011. Of these, 213 (38.9%) patients experienced 306 episodes of chemotherapy delays. The main documented reasons for the chemotherapy delay were neutropenia (84/306, 27.4%), fever or infection (73/306, 23.9%) and thrombocytopenia (26/306, 8.5%). Independent risk factors for chemotherapy delays were upper respiratory infections (OR 1.87, 95% CI 1.27-2.76), lymphopenia, prior hospitalization, peripheral vascular disease and colon cancer relative to hematologic cancer. In the adjusted analysis focusing on chemotherapy delays due to infection alone, upper respiratory infections (OR 5.25, 95% I 2.81-9.84) and age were significant independent risk factors. Mild respiratory infections were associated with chemotherapy delays. Our results should encourage modalities to prevent influenza and other upper respiratory infections among cancer patients. Copyright © 2014 The British Infection Association. Published by Elsevier Ltd. All rights reserved.
    Journal of Infection 10/2014; 70(3). DOI:10.1016/j.jinf.2014.10.008 · 4.02 Impact Factor
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    ABSTRACT: Background: Data on the relative efficacy of beta-lactam/beta-lactamase inhibitors (BL/BLIs) versus carbapenems are scant. Methods: This is a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing any BL/BLI versus any carbapenem for the treatment of sepsis. The primary outcome was all-cause mortality. A broad search was conducted with no restrictions on language, publication status or date. Two reviewers independently applied the inclusion criteria and extracted the data. Assessment of risk of bias was performed using the domain-based approach. Subgroup analyses were used to investigate heterogeneity and focus on patient groups more likely to harbour ESBL-positive bacteria. Risk ratios (RRs) with 95% CIs were calculated and pooled. Results: Thirty-one RCTs were included. There was no difference between BL/BLIs and carbapenems in terms of mortality (RR 0.98, 95% CI 0.79-1.20), without heterogeneity. No differences were observed with regard to clinical or microbiological failure and bacterial superinfections. The results were not affected by risk of bias. No differences were detected in the subgroups of patients with nosocomial infections, Gram-negative infections and neutropenic fever. Adverse events requiring discontinuation were more common with BL/BLIs, on account of an increased incidence of diarrhoea. However, Clostridium difficile-associated diarrhoea (RR 0.29, 95% CI 0.10-0.87) was more frequent with carbapenems and seizures were more frequent with imipenem (RR 0.21, 95% CI 0.05-0.93). Conclusions: No differences in efficacy between BL/BLIs and carbapenems exist in RCTs including patient populations with a certain, albeit unknown, rate of ESBL-positive bacteria causing infections.
    Journal of Antimicrobial Chemotherapy 09/2014; 70(1). DOI:10.1093/jac/dku351 · 5.44 Impact Factor
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    ABSTRACT: Background and aims: The diagnosis of patients with fever of unknown origin (FUO) remains a challenging medical problem. We aimed to assess the diagnostic contribution of 18-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET)/computed tomography (CT) for the evaluation of FUO. Methods: We performed a 4-year retrospective single-center study of all hospitalized patients that underwent FDG-PET/CT for evaluation of FUO. The final diagnosis of the febrile disease was based on clinical, microbiological, radiological and pathological data available at the final follow-up. Predictors for a contributory exam were sought. Results: One hundred and twelve patients underwent FDG-PET/CT for the investigation of FUO in the years 2008-2012 and were included in the study. A final diagnosis was determined in 83 patients (74%) and included: infectious disease in 49 patients (43%), non-infectious inflammatory disease in 17 patients (16%), malignancies in 15 patients (14%), other diagnoses in 2 patients (1.7%), FUO resolved with no diagnosis and no evidence of disease during a 6-month follow-up in 23 patients (20%), and death with fever and with no diagnosis in 6 patients (5%). Seventy-four FDG-PET/CT studies (66%) were considered clinically helpful and contributory to diagnosis (46% positive contributory value and 20.5% contributory to exclusion of diagnosis). PET/CT had a sensitivity of 72.2%, a specificity of 57.5%, a positive predictive value (PPV) of 74.2% and a negative predictive value (NPV) of 53.5%. On multivariable analysis, significant predictors of a positive PET/CT contributory to diagnosis were a short duration of fever and male gender. Conclusions: PET/CT is an important diagnostic tool for patients with FUO.
    QJM: monthly journal of the Association of Physicians 09/2014; 108(4). DOI:10.1093/qjmed/hcu193 · 2.46 Impact Factor
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    ABSTRACT: Background: Venous thromboembolism (VTE) is a feared complication during hospitalization. The practice of administering pharmacological prophylaxis is highly endorsed despite failure of studies to show reduction in mortality. Aim: To determine the benefit of VTE prophylaxis in acutely ill medical patients with sepsis. Methods: A prospective cohort, with enrollment between January 2010 and April 2011. Patients were detected in four medicine departments at a university-affiliated hospital and followed for 90 days for pre-specified outcomes. We included all septic patients at high VTE risk defined by Padua score ≥ 4. The primary outcome was 30-day mortality. Incidence of pulmonary embolism, deep vein thrombosis or major bleeding episodes at 30 and 90 days, and 90-day mortality were secondary outcomes. Results: A total of 1540 patients were identified, of which 720 (55%) were at high risk for VTE and included. A total of 213 (29.6%) patients received prophylaxis. VTE occurred in 6 control patients and 2 treated (0.9 and 1.2%, respectively, RR 0.79, CI: 0.16–3.95). Major bleeding events occurred in 4 (0.8%) control and 7 (3.3%) treated patients (RR 4.1, CI: 1.24–14.08, P = 0.01). After adjusting for covariates, VTE prophylaxis conferred no 30- or 90-day mortality benefit (OR 1.24, CI: 0.79–1.93 and OR 1.47, CI: 0.99–2.17, respectively). Lack of significant benefit with prophylaxis persisted after propensity-score matching (OR for 30-day mortality 1.01, CI: 0.66–1.55). Conclusions: In acutely ill inpatients with sepsis, no significant benefit was demonstrated for VTE prophylaxis, with higher rates of bleeding. The risk-benefit ratio of this intervention should be carefully examined.
    QJM: monthly journal of the Association of Physicians 09/2014; 108(3). DOI:10.1093/qjmed/hcu183 · 2.46 Impact Factor
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    ABSTRACT: Cholera is an acute watery diarrhoea caused by infection with the bacterium Vibrio cholerae, which if severe can cause rapid dehydration and death. Effective management requires early diagnosis and rehydration using oral rehydration salts or intravenous fluids. In this review, we evaluate the additional benefits of treating cholera with antimicrobial drugs.
    Cochrane database of systematic reviews (Online) 06/2014; 6(6):CD008625. DOI:10.1002/14651858.CD008625.pub2 · 5.70 Impact Factor
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    Leonard Leibovici · Mical Paul
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    ABSTRACT: A recent Cochrane systematic review shook the base of evidence on neuraminidase inhibitors (NIs) claiming that NIs have negligible efficacy in the treatment of influenza(1) . An individual patient data meta-analysis seemingly contradicts these findings(2) . The public, physicians, policy makers and governments are now struggling to understand how to translate these findings to clinical practice. This article is protected by copyright. All rights reserved.
    Clinical Microbiology and Infection 06/2014; 20(12). DOI:10.1111/1469-0691.12708 · 5.20 Impact Factor
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    ABSTRACT: Carbapenem-resistant Gram-negative bacteria (CR-GNB) represent an increasing hazard in healthcare settings. A central question concerning the treatment of invasive infections caused by CR-GNB involves the use of combination therapy. Potential advantages of combination therapy include improved efficacy due to synergy, while the disadvantages include adverse events and increased antibiotic use with a potential drive towards resistance. Several observational studies have examined whether combination therapy offers an advantage over colistin/polymyxin monotherapy. We highlight the inherent limitations of these studies related to their observational design and sample size to show why they do not at present provide an answer to the question of combination versus monotherapy. This distinction is important to guide clinical practice until solid evidence has been obtained and to enable the recruitment of patients into randomized controlled trials. A few randomized controlled trials examining specific combinations have recently been completed or are ongoing. Currently, however, there is no evidence-based support for most combination therapies against CR-GNB, including colistin/carbapenem combination therapy.
    Journal of Antimicrobial Chemotherapy 05/2014; 69(9). DOI:10.1093/jac/dku168 · 5.44 Impact Factor
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    The Lancet Respiratory Medicine 05/2014; 2(5):395-404. DOI:10.1016/S2213-2600(14)70041-410 · 9.63 Impact Factor

Publication Stats

4k Citations
1,112.89 Total Impact Points


  • 2014–2015
    • Technion - Israel Institute of Technology
      • Ruth and Bruce Rappaport Faculty of Medicine
      H̱efa, Haifa, Israel
    • Tel Aviv Sourasky Medical Center
      • Geriatrics
      Tell Afif, Tel Aviv, Israel
  • 2004–2015
    • Rambam Medical Center
      H̱efa, Haifa, Israel
  • 2003–2015
    • Tel Aviv University
      • • Faculty of Medicine
      • • Sackler Faculty of Medicine
      • • Department of Neurology
      Tell Afif, Tel Aviv, Israel
  • 2003–2012
    • Rabin Medical Center
      • Department of Cardiology
      Tell Afif, Tel Aviv, Israel
  • 2010
    • Johns Hopkins Bloomberg School of Public Health
      • Department of International Health
      Baltimore, Maryland, United States
  • 2007
    • University of Bristol
      Bristol, England, United Kingdom