Background: Allogeneic hematopoietic cell transplant (allo-HCT) represents a definitive therapy for a variety of hematological diseases. Immunosuppressive therapy following allo-HCT and graft-vs-host disease (GVHD) render the patient susceptible to infectious complications, including invasive pneumococcal disease. Post-allo-HCT pneumococcal vaccination is recommended 3-6 months after transplant in a multi-dose series to help prevent pneumococcal disease. Aims: V114 is a 15-valent pneumococcal conjugate vaccine (PCV) approved in adults, containing all 13 serotypes in Prevnar 13™ (PCV13; contains serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F) as well as epidemiologically important serotypes 22F and 33F. This study evaluated safety and immunogenicity of V114 when given to allo-HCT recipients. Methods: Individuals ≥3 years of age were randomized 1:1 to receive 3 doses of V114 or PCV13 in one-month intervals starting 3-6 months after allo-HCT. At 12 months after HCT, participants received either PNEUMOVAXTM 23 or a fourth dose of PCV if they experienced chronic GVHD. All participants or their legal representatives provided informed consent at enrollment. Primary safety objective was to evaluate the proportion of participants with adverse events (AEs) within each vaccination group for 3 to <18 years old and ≥18 years old age groups. Primary immunogenicity objective was to evaluate serotype-specific immunoglobulin G (IgG) geometric mean concentrations (GMCs) for all 15 V114 serotypes at 30 days following the third PCV dose (Day 90) in each vaccination group. A key secondary objective was to evaluate opsonophagocytic activity (OPA) geometric mean titers (GMTs) for all V114 serotypes at Day 90. Results: A total of 274 subjects (14 children [3 to <18 years of age] and 260 adults ≥18 years old) were enrolled and vaccinated in the study. The proportion of participants with systemic AEs and serious AEs after any dose of study vaccine were generally comparable between intervention groups in the pediatric and adult cohorts. V114 recipients reported a higher proportion of injection-site AEs and vaccine-related systemic AEs compared to PCV13 in the adult cohort. Of all vaccinated participants, 32.4% experienced serious AEs during the study (28.8% in V114 group, 36.3% in PCV13 group). Seventeen participants (5.8% in V114 group, 6.7% in PCV13 group) died during the study. None of the deaths were determined by the investigator to be related to study vaccines. For both IgG GMCs (Table 1) and OPA GMTs, V114 was generally comparable to PCV13 for the 13 shared serotypes, and higher for serotypes 22F and 33F at Day 90. Image:Summary/Conclusion: V114 was well tolerated in allo-HCT recipients with a generally comparable safety profile to PCV13 for both pediatric and adult participants. Despite the immunocompromised status of the participants, the study vaccines induced serotype-specific immunogenicity and V114 induced generally comparable responses to PCV13 by IgG GMCs and OPA for the 13 shared serotypes at Day 90. In addition, V114 induced higher antibody responses than PCV13 for serotypes unique to V114 (22F and 33F). Study results support the use of V114 in allo-HCT recipients.

BACKGROUND:The performance of the galactomannan enzyme immunoassay (GM-EIA) is impaired in patients receiving mould-active antifungal therapy. The impact of mould-active antifungal therapy on Aspergillus PCR testing needs to be determined. OBJECTIVES:To determine the influence of anti-mould prophylaxis (AMP) on the performance of PCR blood testing to aid the diagnosis of proven/probable invasive aspergillosis (IA). METHODS:As part of the systematic review and meta-analysis of 22 cohort studies investigating Aspergillus PCR blood testing in 2912 patients at risk of IA, subgroup analysis was performed to determine the impact of AMP on the accuracy of Aspergillus PCR. The incidence of IA was calculated in patients receiving and not receiving AMP. The impact of two different positivity thresholds (requiring either a single PCR positive test result or ≥2 consecutive PCR positive test results) on accuracy was evaluated. Meta-analytical pooling of sensitivity and specificity was performed by logistic mixed-model regression. RESULTS:In total, 1661 (57%) patients received prophylaxis. The incidence of IA was 14.2%, significantly lower in the prophylaxis group (11%-12%) compared with the non-prophylaxis group (18%-19%) (P < 0.001). The use of AMP did not affect sensitivity, but significantly decreased specificity [single PCR positive result threshold: 26% reduction (P = 0.005); ≥2 consecutive PCR positive results threshold: 12% reduction (P = 0.019)]. CONCLUSIONS:Contrary to its influence on GM-EIA, AMP significantly decreases Aspergillus PCR specificity, without affecting sensitivity, possibly as a consequence of AMP limiting the clinical progression of IA and/or leading to false-negative GM-EIA results, preventing the classification of probable IA using the EORTC/MSGERC definitions.

In this issue, Tau et al. discuss the results of a systematic review about reporting infections in clinical trials of individuals with haematological malignancies [1]. The authors show the need for improving the way of reporting these complications, otherwise new drugs may become available for routine use while their main complications are still unknown. This caveat results in a lack of management strategies before the routine use of a new drug. This concern had been previously discussed in the consensus document of the European Hematology Association Roadmap for Research in Hematology [2] and more recently by the European Conference on Infections in Leukaemia in a position paper by G.

We read with interest the recent network meta-analysis published by Horita et al. comparing different β-lactams in the empirical treatment of febrile neutropenia (FN) [[1]Horita N. Shibata Y. Watanabe H. Namkoong H. Kaneko T. Comparison of antipseudomonal β-lactams for febrile neutropenia empiric therapy: systematic review and network meta-analysis.Clin Microbiol Infect. 2017; 23: 723-729Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar]. We consider that the authors draw debatable conclusions that could encourage unjustifiably wide use of imipenem/cilastatin in individuals with FN. Another meta-analysis, published in 2010 [[2]Paul M. Yahav D. Bivas A. Fraser A. Leibovici L. Anti-pseudomonal β-lactams for the initial, empirical, treatment of febrile neutropenia: comparison of β-lactams.Cochrane Database Syst Rev. 2010; : CD005197PubMed Google Scholar] on the same issue, drew different conclusions, showing lower all-cause mortality with piperacillin/tazobactam versus cefepime or carbapenems. Several reasons can explain these different findings. Most obviously, some studies included by Horita et al., simply post-dated Paul et al.; but, perhaps more importantly, the newly available studies included by Horita et al. are often from high-resistance countries and often analysed piperacillin/tazobactam, whereas much of the imipenem/cilastatin data come from relatively old studies. As resistance varies with place and time, these factors have major potential impact. Overall, 15 studies representing 4026 patients and comparing piperacillin/tazobactam with other antibiotics were included in Horita et al.’s meta-analysis, but not in that of Paul et al.; ten of these were published since 2010, variously originating from Turkey, India, Japan, China and Spain. A recent multinational study of bacteraemia in individuals undergoing haematopoietic stem cell transplants found significantly higher rates of resistance to non-carbapenem β-lactams among Gram-negative rods (GNRs) isolated from patients in southeast Europe (55.3%) or China (76%) versus those in northwest Europe (27.6%) [[3]Averbuch D. Tridello G. Hoek J. Mikulska M. Akan H. Yanez San Segundo L. et al.Antimicrobial resistance in gram-negative rods causing bacteremia in haematopoietic stem cell transplant patients: intercontinental prospective study of Infectious Diseases Working Party of the European Bone Marrow Transplantation group.Clin Infect Dis. 2017; 65: 1819-1828Crossref PubMed Scopus (128) Google Scholar]. In this study, 33.9%, 56.5% and 52.0% of GNR reported from Spain, Turkey and China, respectively, were resistant to non-carbapenem anti-Pseudomonas penicillin β-lactamase inhibitors. In an Indian study, fully 82.7% of Escherichia coli and 74.3% of Klebsiella spp. isolated from individuals with cancer were extended spectrum β-lactamase producers [[4]Abdul K. Vidyalakshmi P. Jayalakshmi V. Poojary I. Susceptibility profile of gram-negative bacteremic isolates to β lactam-β lactamase inhibitor agents in comparison to other antibiotics.Indian J Cancer. 2014; 51: 450-452Crossref PubMed Scopus (2) Google Scholar]. One would expect to see an advantage for imipenem/cilastatin over other β-lactams at sites with such high rates of resistance, where empirical treatment with piperacillin/tazobactam may be insufficient. Basing the approach to FN on local epidemiology is crucial. In our recent study in haematopoietic stem cell transplant patients, a half of GNR were resistant to non-carbapenem β-lactams [[3]Averbuch D. Tridello G. Hoek J. Mikulska M. Akan H. Yanez San Segundo L. et al.Antimicrobial resistance in gram-negative rods causing bacteremia in haematopoietic stem cell transplant patients: intercontinental prospective study of Infectious Diseases Working Party of the European Bone Marrow Transplantation group.Clin Infect Dis. 2017; 65: 1819-1828Crossref PubMed Scopus (128) Google Scholar]; however, the rates in individual countries ranged from 0% to 100%. Underpinning the high rates of resistance among GNRs in some parts of the world are changes in the global molecular epidemiology, mainly since 2000, notably including the proliferation of Escherichia coli ST131 and the common co-presence of CTX-M-15 (an extended spectrum β-lactamase) with OXA-1/30 (a sulphone/clavam-resistant penicillinase) enzymes in this and other Enterobacteriaceae. In some European regions, over 50% of bloodstream E. coli isolates were reported to be resistant to third-generation cephalosporins in the 2016 WHO Antimicrobial Resistance report (http://www.euro.who.int/__data/assets/pdf_file/0005/354434/WHO_CAESAR_AnnualReport_2017.pdf?ua=1). Piperacillin/tazobactam may be less effective in this situation and most (19/23) of these studies assessing piperacillin/tazobactam in Horita et al.’s meta-analysis were published after 2000. Ten studies included in Horita et al.’s meta-analysis compared imipenem/cilastatin to other antibiotics; these included 2156 patients. Seven of these studies (1496 patients, 70%) were published between 1990 and 2004, before the global spread of carbapenem-resistant Enterobacteriaceae. Several countries have, largely since 2007, seen proliferation of carbapenemases, though the predominant types (KPC, OXA-48, VIM, NDM or IMP) vary with the particular country. Thirteen of the 50 studies selected by Horita et al. were published between 1990 and 2000. Significant changes occurred in bacterial resistance since 90s to present day. This is a common problem of network meta-analysis on antibacterials, where efficacy may change with time and place. In simple language, this means that one must be very wary of statistical comparison of agents that were not compared head-to-head in the same time and place. In the present case, mortality data on imipenem, based on studies mainly published before the emergence of carbapenem-resistance, are compared with mortality data on piperacillin/tazobactam based on more recent studies, mainly from countries with high rates of extended spectrum β-lactamase infections. Another concern is the dosing regimens of β-lactams, which was not considered in Horita et al.’s meta-analysis. Individuals with FN have an increased volume of distribution and increased clearance, resulting in a decreased time above MIC. Therefore, using a maximal dosage is crucial. In the studies selected by Horita et al., piperacillin/tazobactam was dosed at 4.5 g thrice daily in 6/23 studies and 24% of the patients, and meropenem was dosed at ≤2 g/day (in adults) in 2/14 studies and 24% of the patients. These regimens, which were not enhanced by prolonged/continuous infusion, may be insufficient. The authors' conclusion that ‘Among guideline-recommend medications, imipenem/cilastatin was related to the highest treatment success rate and the lowest all-cause death’ may encourage preferential use of imipenem/cilastatin as the primary choice for any FN. However, no significant differences were reported according to the primary end point (treatment success without modification) between cefepime, meropenem, imipenem/cilastatin and piperacillin/tazobactam, nor for a secondary end point (all-cause death) between meropenem, imipenem/cilastatin, ceftazidime and piperacillin/tazobactam. Moreover, there are no significant differences in the spectrum of coverage between meropenem and imipenem/cilastatin. In conclusion, the ECIL group wishes to reiterate its previous position that, although we have no doubt as to the efficacy and safety profile of imipenem/cilastatin in patients with FN, carbapenems should, whenever possible, be avoided in individuals without severe clinical presentation and risk factors for bacterial resistance to other agents, so as to preserve their activity [[5]Averbuch D. Orasch C. Cordonnier C. Livermore D.M. Mikulska M. Viscoli C. et al.European guidelines for empirical antibacterial therapy for febrile neutropenic patients in the era of growing resistance: summary of the 2011 4th European Conference on Infections in Leukemia.Haematologica. 2013; 98: 1826-1835Crossref PubMed Scopus (351) Google Scholar]. The wide range of resistance rates among GNRs in different countries warrants a customized approach in patients with FN, combined with rigorous infection control in settings where resistance has become or is becoming prevalent. Universal deployment of carbapenems without de-escalation in all individuals with FN, half of whom have neither clinical nor microbiological infection, is only likely to lead to an increase in carbapenem-resistant infections, and should be discouraged. DA, CO, MM, IG, WK, GK, OM, DE, MA, TC and CC reported no conflicts of interests. DL and CV reported on the conflicts of interests outside the submitted work in the COI form attached. No funding was received for this manuscript.

Prophylaxis with fluoroquinolones (FQ) during prolonged neutropenia has been standard of care in many centres based on the results of meta-analyses and a large prospective study performed in Italy in patients with haematological malignancies. A meta-analysis from 2005, which included studies published between 1973 and 2005, found significantly lower rates of mortality, infections, and fever episodes in patients receiving FQ prophylaxis [[1]Gafter-Gvili A. Fraser A. Paul M. van de Wetering M. Kremer L. Leibovici L. Antibiotic prophylaxis for bacterial infections in afebrile neutropenic patients following chemotherapy.Cochrane Database Syst Rev. 2005; CD004386PubMed Google Scholar]. The randomized study by Bucaneve and colleagues reported significantly lower rates of fever episodes (65% vs. 85%) and bacteraemia (18% vs. 34%) in patients receiving prophylaxis with levofloxacin, with no significant impact on mortality (3% vs. 5%) [[2]Bucaneve G. Micozzi A. Menichetti F. Martino P. Dionisi M.S. Martinelli G. et al.Levofloxacin to prevent bacterial infection in patients with cancer and neutropenia.N Engl J Med. 2005; 353: 977-987Crossref PubMed Scopus (504) Google Scholar]. An updated meta-analysis, which incorporated these data, confirmed the benefit of FQ on fever, bacteraemia, and mortality, with a number-needed-to-treat to prevent one death of 55 [[3]Leibovici L. Paul M. Cullen M. Bucaneve G. Gafter-Gvili A. Fraser A. et al.Antibiotic prophylaxis in neutropenic patients: new evidence, practical decisions.Cancer. 2006; 107: 1743-1751Crossref PubMed Scopus (155) Google Scholar]. A meta-analysis limited only to stem cell transplant patients, mainly autologous (ASCT), who were not included in the Bucaneve trial, found lower rates of bacteraemia and febrile episodes but no impact on mortality [[4]Kimura S. Akahoshi Y. Nakano H. Ugai T. Wada H. Yamasaki R. et al.Antibiotic prophylaxis in hematopoietic stem cell transplantation. A meta-analysis of randomized controlled trials.J Infect. 2014; 69: 13-25Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar]. However, a decade later, considering the threat of increasing antimicrobial resistance worldwide, the utility of FQ prophylaxis has been questioned for two main reasons. First, doubts about its efficacy were prompted by high rates of resistance to FQ, reported both in the community and in the hospital setting. Indeed, resistance to FQ in strains from invasive infections in 2016 reached over 40% for E. coli in Slovakia, Bulgaria, Italy, and Cyprus, and over 60% for K. pneumonia in Romania, Slovakia, Poland, and Greece [[5]Control ECfDPa Antimicrobial resistance surveillance in Europe 2016. Annual report of the European antimicrobial resistance surveillance network (ears-net). ECDC, Stockholm2017Google Scholar]. As patients with haematological malignancies usually undergo repeated cycles of in-patient chemotherapy, they are likely to be colonized by FQ-resistant pathogens. Second, the risk of inducing or selecting multidrug-resistant (MDR) strains by prolonged and repeated exposure to FQ has been reported. Indeed, the possibility of FQ promoting infections caused by multidrug-resistant pathogens, such as those producing extended spectrum β-lactamase (ESBL), has been observed [[6]Mendelson G. Hait V. Ben-Israel J. Gronich D. Granot E. Raz R. Prevalence and risk factors of extended-spectrum beta-lactamase-producing escherichia coli and klebsiella pneumoniae in an israeli long-term care facility.Eur J Clin Microbiol Infect Dis. 2005; 24: 17-22Crossref PubMed Scopus (80) Google Scholar], particularly in settings with a high prevalence of resistant strains [7Garnica M. Nouer S.A. Pellegrino F.L. Moreira B.M. Maiolino A. Nucci M. Ciprofloxacin prophylaxis in high risk neutropenic patients: effects on outcomes, antimicrobial therapy and resistance.BMC Infect Dis. 2013; 13: 356Crossref PubMed Scopus (47) Google Scholar, 8Mikulska M. Averbuch D. Tissot F. Cordonnier C. Akova M. Calandra T. et al.Fluoroquinolone prophylaxis in haematological cancer patients with neutropenia: ECIL critical appraisal of previous guidelines.J Infect. 2018; 76: 20-37Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar]. Indirect evidence concerning this issue came from a large recent study which included 65 SCT centres from 25 countries (Europe, Australia, Asia) reporting data on 655 episodes of Gram-negative bacteraemia [[9]Averbuch D. Tridello G. Hoek J. Mikulska M. Akan H. Yanez San Segundo L. et al.Antimicrobial resistance in gram-negative rods causing bacteremia in hematopoietic stem cell transplant recipients: intercontinental prospective study of the infectious diseases working party of the european bone marrow transplantation group.Clin Infect Dis. 2017; 65: 1819-1828Crossref PubMed Scopus (128) Google Scholar]. This observational trial reported that 45% of ASCT centres provided FQ prophylaxis. The rates of resistance to β-lactams other than carbapenems and MDR were significantly higher in centres providing versus those not providing fluoroquinolone prophylaxis (respectively, 36% vs. 13%, p 0.002 and MDR 35% vs. 8%, p <0.001) [[9]Averbuch D. Tridello G. Hoek J. Mikulska M. Akan H. Yanez San Segundo L. et al.Antimicrobial resistance in gram-negative rods causing bacteremia in hematopoietic stem cell transplant recipients: intercontinental prospective study of the infectious diseases working party of the european bone marrow transplantation group.Clin Infect Dis. 2017; 65: 1819-1828Crossref PubMed Scopus (128) Google Scholar]. In this issue of Clinical Microbiology and Infection, Yeshurun et al. [[10]Yeshurun M. Vaxman I. Shargian L. Yahav D. Bishara J. Pasvolsky O. et al.Antibacterial prophylaxis with ciprofloxacin for patients with multiple myeloma and lymphoma undergoing autologous haematopoietic cell transplantation: a quasi-experimental single centre before-after study.Clin Microbiol Infect. 2018; 24: 749-754Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar] report findings of a single-centre retrospective study on the effect of ciprofloxacin prophylaxis discontinuation on infectious complications in patients with multiple myeloma and lymphoma undergoing ASCT. The authors compared febrile episodes, infectious complications (bacteraemia, pneumonia, and Clostridium difficile associated disease (CDAD)), and mortality in 177 patients transplanted between March 2007 and October 2012 who received prophylaxis with ciprofloxacin versus 179 patients transplanted between October 2012 and July 2016 who did not receive any antibiotic prophylaxis. During the second period, they observed higher rates of febrile neutropenia (83.1% vs. 90.4%, p 0.002), bacteraemia (4.5% vs. 15%, p <0.0001), and pneumonia (6.2% vs. 12.3%, p 0.04). The rate of CDAD did not change significantly (2.8% vs. 6.7%, p 0.08), and mortality was similar (2.3% vs. 1.1% p 0.4). The authors concluded that patients with multiple myeloma and lymphoma undergoing ASCT may benefit from antibacterial prophylaxis with ciprofloxacin. Association between FQ prophylaxis and lower rate of bacteraemia in ASCT recipients, particularly with multiple myeloma, has been recently reported by other groups [11Satlin M.J. Vardhana S. Soave R. Shore T.B. Mark T.M. Jacobs S.E. et al.Impact of prophylactic levofloxacin on rates of bloodstream infection and fever in neutropenic patients with multiple myeloma undergoing autologous hematopoietic stem cell transplantation.Biol Blood Marrow Transpl. 2015; 21: 1808-1814Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 12Girmenia C. Bertaina A. Piciocchi A. Perruccio K. Algarotti A. Busca A. et al.Incidence, risk factors and outcome of pre-engraftment gram-negative bacteremia after allogeneic and autologous hematopoietic stem cell transplantation: an Italian prospective multicenter survey.Clin Infect Dis. 2017; 65: 1884-1896Crossref PubMed Scopus (73) Google Scholar]. A recent literature review on FQ prophylaxis in haematology patients with neutropenia performed by the European Conference on Infections in Leukemia (ECIL) group [[8]Mikulska M. Averbuch D. Tissot F. Cordonnier C. Akova M. Calandra T. et al.Fluoroquinolone prophylaxis in haematological cancer patients with neutropenia: ECIL critical appraisal of previous guidelines.J Infect. 2018; 76: 20-37Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar], found that FQ might still prevent infectious episodes, particularly in settings of low prevalence of MDR strains, such as in the Yeshurun et al. cohort, in which no patient was colonized with any MDR strain [[10]Yeshurun M. Vaxman I. Shargian L. Yahav D. Bishara J. Pasvolsky O. et al.Antibacterial prophylaxis with ciprofloxacin for patients with multiple myeloma and lymphoma undergoing autologous haematopoietic cell transplantation: a quasi-experimental single centre before-after study.Clin Microbiol Infect. 2018; 24: 749-754Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar]. Other recent studies with similar retrospective comparisons with historical cohorts evaluated the effect of discontinuing prophylaxis. While some, but not all, reported higher rates of bacteraemia with no prophylaxis, none of them, even one that included 1987 patients, found any difference in mortality [[8]Mikulska M. Averbuch D. Tissot F. Cordonnier C. Akova M. Calandra T. et al.Fluoroquinolone prophylaxis in haematological cancer patients with neutropenia: ECIL critical appraisal of previous guidelines.J Infect. 2018; 76: 20-37Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar]. The crucial issue is the clinical benefit of a reduction in fever and/or bacteraemia episodes, usually caused by susceptible strains, in times of the need of antibiotic stewardship due to a worldwide increase in MDR strains. Yeshurun et al. assumed that as bacteraemia was associated with higher mortality (8.6% vs. 0.8% at 30 days) and ciprofloxacin prophylaxis was associated with a lower rate of bacteraemia, the prophylaxis would result in lower mortality. However, the mortality in neutropenic patients with bacteraemia is influenced mostly by the time between the onset of infection and the administration of appropriate antibiotic therapy [[13]Trecarichi E.M. Tumbarello M. Spanu T. Caira M. Fianchi L. Chiusolo P. et al.Incidence and clinical impact of extended-spectrum-beta-lactamase (esbl) production and fluoroquinolone resistance in bloodstream infections caused by escherichia coli in patients with hematological malignancies.J Infect. 2009; 58: 299-307Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar]. Bacteraemia episodes that can be prevented by ciprofloxacin are typically caused by susceptible bacteria, and as such, empirical therapy would be effective against them and they should not result in increased mortality. Bacteraemia-associated mortality is usually caused by MDR pathogens, which are unlikely to be prevented by FQ [12Girmenia C. Bertaina A. Piciocchi A. Perruccio K. Algarotti A. Busca A. et al.Incidence, risk factors and outcome of pre-engraftment gram-negative bacteremia after allogeneic and autologous hematopoietic stem cell transplantation: an Italian prospective multicenter survey.Clin Infect Dis. 2017; 65: 1884-1896Crossref PubMed Scopus (73) Google Scholar, 14Mikulska M. Raiola A.M. Galaverna F. Balletto E. Borghesi M.L. Varaldo R. et al.Pre-engraftment bloodstream infections after allogeneic hematopoietic cell transplantation: impact of t cell-replete transplantation from a haploidentical donor.Biol Blood Marrow Transpl. 2018; 24: 109-118Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar]. For example, in a recent multicentre study, 78% of carbapenem-resistant Enterobacteriaceae were resistant to FQ [[9]Averbuch D. Tridello G. Hoek J. Mikulska M. Akan H. Yanez San Segundo L. et al.Antimicrobial resistance in gram-negative rods causing bacteremia in hematopoietic stem cell transplant recipients: intercontinental prospective study of the infectious diseases working party of the european bone marrow transplantation group.Clin Infect Dis. 2017; 65: 1819-1828Crossref PubMed Scopus (128) Google Scholar]. This study also noted that the negative impact on survival was mainly caused by infections caused by resistant Gram-negative pathogens, which are unlikely to be prevented by FQ prophylaxis. A recent observational study from Italy which included 1625 ASCT recipients, reported that infections caused by resistant pathogens were predominantly responsible for increased mortality [[12]Girmenia C. Bertaina A. Piciocchi A. Perruccio K. Algarotti A. Busca A. et al.Incidence, risk factors and outcome of pre-engraftment gram-negative bacteremia after allogeneic and autologous hematopoietic stem cell transplantation: an Italian prospective multicenter survey.Clin Infect Dis. 2017; 65: 1884-1896Crossref PubMed Scopus (73) Google Scholar]. The probability of survival at 4 months from transplant in 1479 patients who did not develop bacteraemia because of Gram-negative bacteria was 97.5%, compared with 98.4% in 63 patients with cephalosporin-susceptible E. coli infection (p 0.66), 93.1% in 29 patients with cephalosporin-non-susceptible but carbapenem-susceptible E. coli infection (p 0.13), but only 66.7% in six patients with carbapenem-resistant K. pneumoniae infections (p <0.0001) [[12]Girmenia C. Bertaina A. Piciocchi A. Perruccio K. Algarotti A. Busca A. et al.Incidence, risk factors and outcome of pre-engraftment gram-negative bacteremia after allogeneic and autologous hematopoietic stem cell transplantation: an Italian prospective multicenter survey.Clin Infect Dis. 2017; 65: 1884-1896Crossref PubMed Scopus (73) Google Scholar]. This might explain the lack of effect of FQ prophylaxis on mortality despite the presence of a reduced rate of infection, reported also in other recent studies [[8]Mikulska M. Averbuch D. Tissot F. Cordonnier C. Akova M. Calandra T. et al.Fluoroquinolone prophylaxis in haematological cancer patients with neutropenia: ECIL critical appraisal of previous guidelines.J Infect. 2018; 76: 20-37Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar]. Two recent guidelines invite the readers to interpret the data in the light of the lack of significant benefit on mortality, and despite a possible reduction in the rate of infection and fever episodes in some settings, they do not recommend FQ prophylaxis [15Slavin M.A. Lingaratnam S. Mileshkin L. Booth D.L. Cain M.J. Ritchie D.S. et al.Use of antibacterial prophylaxis for patients with neutropenia. Australian consensus guidelines 2011 steering committee.Intern Med J. 2011; 41: 102-109Crossref PubMed Scopus (41) Google Scholar, 16Klastersky J. de Naurois J. Rolston K. Rapoport B. Maschmeyer G. Aapro M. et al.Management of febrile neutropenia: ESMO clinical practice guidelines.Ann Oncol. 2016; 27: v111-v118Crossref PubMed Scopus (354) Google Scholar]. This cautious policy is in agreement with what we, on behalf of the ECIL group, have recently published [[8]Mikulska M. Averbuch D. Tissot F. Cordonnier C. Akova M. Calandra T. et al.Fluoroquinolone prophylaxis in haematological cancer patients with neutropenia: ECIL critical appraisal of previous guidelines.J Infect. 2018; 76: 20-37Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar]. In conclusion, it is unlikely that FQ prophylaxis would reduce mortality, because (1) infections by susceptible strains are easily treated with standard empirical therapy, and (2) mortality is mainly driven by infections caused by pathogens resistant to standard therapy employed in febrile neutropenia and to FQs. In the era of increasing antibiotic resistance, even in settings with low prevalence of MDR bacteria so far, routine use of FQ prophylaxis should be reconsidered. Further research should focus on rapid identification of infecting pathogens and their susceptibility profile to allow for early start of adequate treatment even in case of resistant bacteria. CC reported no conflicts of interests. MM reported on the conflicts of interests outside the submitted work in the COI form attached. No funding was received for this manuscript. Antibacterial prophylaxis with ciprofloxacin for patients with multiple myeloma and lymphoma undergoing autologous haematopoietic cell transplantation: a quasi-experimental single-centre before-after studyClinical Microbiology and InfectionVol. 24Issue 7PreviewWe aimed to study whether ciprofloxacin prophylaxis reduces infectious complications in patients undergoing autologous haematopoietic cell transplantation (AHCT). Full-Text PDF Open Archive

ABSTRACT Introduction: Invasive fungal infections (IFIs) following allogeneic hematopoietic stem cell transplantation (alloHSCT) are associated with a high mortality, and accordingly most alloHSCT recipients receive prophylaxis with antifungal agents. Despite some improvement in outcomes of IFIs over time, they continue to represent substantial clinical risk, mortality, and financial burden. Areas covered: We review the main pathogens responsible for IFIs in recipients of alloHSCT, current treatment recommendations, and discuss clinical and economic considerations associated with voriconazole prophylaxis of IFIs in these patients. Expert commentary: The clinical efficacy of voriconazole appears to be at least equivalent to other antifungal treatments, and generally well tolerated. Overall, benefit-risk balance is favorable, and findings from cost-effectiveness analyses support the use of voriconazole prophylaxis of IFIs in recipients of alloHSCT.

Pneumocystis jirovecii pneumonia (PCP) is a life-threatening infection in hematology. Although occasionally reported, the role of interhuman transmission of P. jirovecii in PCP, compared to that of reactivation, remains an unresolved question; the recommendation to isolate PCP patients in the hematology ward are not well evidence-based. Following an unexpected increase in the number of febrile pneumonia patients with P. jirovecii DNA detected in respiratory samples in our hematology ward, we explored 12 consecutive patients from November 2015 to May 2016. Genotyping of P jirovecii was performed using microsatellite markers. The frequency of simultaneous occupancy of these 12 patients in the same unit on the same day from 4 months prior to the first diagnosis was recorded. In three patients, the P. jirovecii genotype could not be determined because DNA was insufficient. One rare single genotype (Gt2) was found in four of the other nine, all allogeneic stem cell transplant recipients. The transmission map showed that these 4 patients had multiple opportunities to meet on the same day (median, 6.5; range, 4-10) at the daycare center. It was much less among the eight non-Gt2 patients (median, 1; range, 0-9; P = 0.048). This study, based on modern molecular technics, strongly suggests that interhuman transmission of P. jirovecii between allogeneic stem cell transplant recipients is possible. P. jirovecii DNA detected in respiratory specimens supports that isolation and respiratory precautions be recommended in such cases in the hematology ward.

Les éruptions cutanées morbilliformes sont fréquentes en période d'aplasie post-chimiothérapie pour des hémopathies malignes ou des cancers solides. Elles posent des problèmes diagnostiques entre les causes infectieuses, les toxidermies, les réactions post-transfusionnelles et les infiltrats de reconstitution lymphocytaire (IRL). Les IRL sont des éruptions cutanées survenant lors de l'aplasie médullaire post-chimiothérapie, lors d'une augmentation des lymphocytes dans la circulation périphérique. Nous rapportons une série de 12 patients (7 hommes et 5 femmes, médiane d'âge : 61 ans), avec un IRL atypique mimant un lymphome T cutané primitif ou une lymphoprolifération cutanée CD30+. Tous les patients présentaient une éruption érythémateuse maculopapuleuse du tronc et des membres associée à une fièvre entre 38 et 39 °C, survenant 5 à 39 jours après le début de la chimiothérapie. Tous les patients, sauf un, avaient reçu une polychimiothérapie pour une leucémie aiguë myéloïde (n = 10) ou un carcinome urothélial avant l'apparition de l'éruption cutanée, et le dernier patient était atteint d'un syndrome lymphoprolifératif auto-immun entraînant une agranulocytose chronique nécessitant un traitement par G-CSF. L'éruption cutanée était associée à une discrète augmentation des leucocytes périphériques et était suivie d'une sortie d'aplasie dans les semaines qui suivaient le diagnostic. L'examen histologique trouvait dans tous les cas un infiltrat lymphocytaire dermique périvasculaire comprenant des lymphocytes atypiques de taille moyenne à grande, CD3+, CD4+ et CD8+, CD25+, ICOS+, PD1−, non cytotoxiques et sans expression significative de FoxP3, avec une expression forte de CD30 dans la majorité des cas (n = 10), suggérant le recrutement de cellules T activées dans la peau, sans clone T dominant identifiable. Chez 6 patients, le diagnostic de lymphome cutané avait été proposé ou suspecté à l'histologie, et seule la confrontation anatomoclinique permettait le diagnostic d'infiltrat de reconstitution lymphocytaire avec une présentation particulière mimant un lymphome T cutané ou une lymphoprolifération T CD30+. Nous rapportons une forme particulière d'IRL caractérisée par la présence de lymphocytes atypiques, activés. Cet aspect histologique particulier pourrait témoigner du recrutement de lymphocytes T activés par un agent viral ou médicamenteux chez des patients peut-être favorisé par un déficit en lymphocytes T régulateurs en rapport avec l'aplasie médullaire chimio-induite. Cet aspect histologique particulier mérite d'être connu par les anatomopathologistes pour éviter de porter à tort un diagnostic de lymphome T cutané ou de lymphoprolifération CD30 dans ce contexte.

We read with interest the Note by Micol et al. [1] challenging ECIL's recommendation to discontinue empirical antibiotics after resolution of fever of unknown origin (FUO) in high-risk haematologic patients despite persistent neutropenia. We reply for the ECIL panel, whose guidance states thatempiric antibiotics can be discontinued after ≥72 hours . . . in [FUO] patients who have been hemodynamically stable since presentation and . . . afebrile for ≥48 hours, irrespective of their neutrophil count or expected duration of neutropenia (BII).

The guidelines for immunization of hematopoietic SCT (HSCT) recipients recommend three doses of antipneumococcal conjugate vaccine (PCV) from 3 to 6 months after transplant, followed by a dose of polysaccharide 23-valent (PPV23) vaccine at 12 months in the case of no GVHD or an additional PCV dose in the case of GVHD. Due to the lack of long-term data in the literature, there is no recommendation for boosts after 12 months. Our goal was to assess the maintenance of the immune response to pneumococcal vaccines in patients vaccinated 10 years ago according to current guidelines. Thirty surviving patients of the IDWP01 (Infectious Diseases Working Party 1) trial were assessed for antibody levels against the seven antigens of the PCV7 and against two of the PPV23-specific antigens. When compared with 24 months after transplant, the immune response did not significantly decrease but with important serotype-specific variability. There was no evidence that an additional dose of PPV23 given to 11/30 patients 2–11 years after transplant was beneficial. In long-term HSCT survivors with no or few GVHD vaccinated against Streptococcus pneumoniae according to the current guidelines, the specific immunity is not fully maintained a decade later. The optimal schedule of antipneumococcal vaccination in HSCT recipients after 12 months remains to be established.