Search

Cefoxitin has demonstrated good in vitro activity against extended spectrum beta-lactamase (ESBL)–producing Escherichia coli (ESBL-Ec) and is regarded as a carbapenem-sparing beta-lactam alternative in urinary tract infections. Its efficacy has never been compared to carbapenems in male UTIs. Our study aimed to compare the clinical and microbiological efficacy of cefoxitin (FOX) and carbapenems (CP) in febrile M-UTI due to ESBL-Ec (F-M-UTI). We conducted a multicenter retrospective cohort study of patients with F-M-UTI treated with FOX or CP as definitive therapy, between January 2013 and June 2015, in six French acute care teaching hospitals. The clinical and microbiological efficacies of FOX and CP were compared using multivariable logistic regression models, adjusting for propensity scores. Of the 66 patients included, 23 patients in FOX group and 27 in CP group had clinical assessment at follow-up. Median follow-up after end of treatment was 63 days (interquartile range 26–114). Clinical success was observed for 17/23 (73.9%) and 22/27 (81.5%) patients and microbiological success for 11/19 (57.9%) and for 6/12 (50.0%) patients in FOX and CP groups respectively. We did not find any significant difference for clinical (OR = 0.90, 95% CI [0.12; 6.70]) neither microbiological (OR = 0.85, 95% CI [0.05; 14.00]) success between CP and FOX groups in univariate and multivariable models. In the FOX group, high dose with use of continuous infusion was associated with clinical success. These results add evidence that FOX is an effective alternative treatment to carbapenems for M-UTI caused by ESBL-Ec, particularly when high doses and continuous infusion are used. [ABSTRACT FROM AUTHOR]

Objectives: In this study, we aimed to assess the efficacy of different ways of administration and types of beta-lactams for hospitalized community-acquired pneumonia (CAP)., Methods: In this post-hoc analysis of randomized controlled trials (RCT) on patients hospitalized for CAP (pneumonia short treatment trial) comparing 3-day vs. 8-day durations of beta-lactams, which concluded to non-inferiority, we included patients who received either amoxicillin-clavulanate (AMC) or third-generation cephalosporin (3GC) regimens, and exclusively either intravenous or oral treatment for the first 3 days (followed by either 5 days of oral placebo or AMC according to randomization). The choice of route and molecule was left to the physician in charge. The main outcome was a failure at 15 days after the first antibiotic intake, defined as temperature >37.9°C, and/or absence of resolution/improvement of respiratory symptoms, and/or additional antibiotic treatment for any cause. The primary outcome according to the route of administration was evaluated through logistic regression. Inverse probability treatment weighting with a propensity score model was used to adjust for non-randomization of treatment routes and potential confounders. The difference in failure rates was also evaluated among several sub-populations (AMC vs. 3GC treatments, intravenous vs. oral AMC, patients with multi-lobar infection, patients aged ≥65 years old, and patients with CURB65 scores of 3-4)., Results: We included 200 patients from the original trial, with 93/200 (46.5%) patients only treated with intravenous treatment and 107/200 (53.5%) patients only treated with oral therapy. The failure rate at Day 15 was not significantly different among patients treated with initial intravenous vs. oral treatment [25/93 (26.9%) vs. 28/107 (26.2%), adjusted odds ratios (aOR) 0.973 (95% CI 0.519-1.823), p 0.932)]. Failure rates at Day 15 were not significantly different among the subgroup populations., Discussion: Among hospitalized patients with CAP, there was no significant difference in efficacy between initial intravenous and exclusive oral treatment., Trial Registration: This trial is registered with ClinicalTrials.gov, NCT01963442., (Copyright © 2024 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Bone and joint infections (BJIs) are complex infections that require precise microbiological documentation to optimize antibiotic therapy. Currently, diagnosis is based on microbiological culture, sometimes complemented by amplification and sequencing of the 16S rDNA gene. Clinical metagenomics (CMg), that is, the sequencing of the entire nucleic acids in a sample, was previously shown to identify bacteria not detected by conventional methods, but its actual contribution to the diagnosis remains to be assessed, especially with regard to 16S rDNA sequencing. In the present study, we tested the performance of CMg in 34 patients (94 samples) with suspected BJIs, as compared to culture and 16S rDNA sequencing. A total of 94 samples from 34 patients with suspicion of BJIs, recruited from two sites, were analyzed by (i) conventional culture, (ii) 16S rDNA sequencing (Sanger method), and (iii) CMg (Illumina Technology). Two negative controls were also sequenced by CMg for contamination assessment. Based on the sequencing results of negative controls, 414 out of 539 (76.7%) bacterial species detected by CMg were considered as contaminants and 125 (23.2%) as truly present. For monomicrobial infections (13 patients), the sensitivity of CMg was 83.3% as compared to culture, and 100% as compared to 16S rDNA. For polymicrobial infections (13 patients), the sensitivity of CMg was 50% compared to culture, and 100% compared to 16S rDNA. For samples negative in culture (8 patients, 21 samples), CMg detected 11 bacteria in 10 samples from 5 different patients. In 5/34 patients, CMg brought a microbiological diagnosis where conventional methods failed, and in 16/34 patients, CMg provided additional information. Finally, 99 antibiotic resistance genes were detected in 24 patients (56 samples). Provided sufficient genome coverage (87.5%), a correct inference of antibiotic susceptibility was achieved in 8/8 bacteria (100%). In conclusion, our study demonstrated that the CMg provides complementary and potentially valuable data to conventional methods of BJIs diagnosis., Competing Interests: GGu and GGe were employed by bioMérieux SA. SF was employed by Genoscreen. ER received consulting fees from Illumina and Pathoquest. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 d’Humières, Gaïa, Gueye, de Lastours, Leflon-Guibout, Maataoui, Duprilot, Lecronier, Rousseau, Gamany, Lescure, Senard, Deconinck, Dollat, Isernia, Le Hur, Petitjean, Nazimoudine, Le Gac, Chalal, Ferreira, Lazarevic, Guigon, Gervasi, Armand-Lefèvre, Schrenzel and Ruppé.)

Importance: Failure of treatment is the most serious complication in community-acquired pneumonia (CAP)., Objective: To assess the potential risk factors for treatment failure in clinically stable patients with CAP., Design, Setting, and Participants: This secondary analysis assesses data from a randomized clinical trial on CAP (Pneumonia Short Treatment [PTC] trial) conducted from December 19, 2013, to February 1, 2018. Data analysis was performed from July 18, 2019, to February 15, 2020. Patients hospitalized at 1 of 16 centers in France for moderately severe CAP who were clinically stable at day 3 of antibiotic treatment were included in the PTC trial and analyzed in the per-protocol trial population., Interventions: Patients were randomly assigned (1:1) on day 3 of antibiotic treatment to receive β-lactam (amoxicillin-clavulanate [1 g/125 mg] 3 times daily) or placebo for 5 extra days., Main Outcomes and Measures: The main outcome was failure at 15 days after first antibiotic intake, defined as a temperature greater than 37.9 °C and/or absence of resolution or improvement of respiratory symptoms and/or additional antibiotic treatment for any cause. The association among demographic characteristics, baseline clinical and biological variables available (ie, at the first day of β-lactam treatment), and treatment failure at day 15 among the per-protocol trial population was assessed by univariate and multivariable logistic regressions., Results: Overall, 310 patients were included in the study; this secondary analysis comprised 291 patients (174 [59.8%] male; mean [SD] age, 69.6 [18.5] years). The failure rate was 26.8%. Male sex (odds ratio [OR], 1.74; 95% CI, 1.01-3.07), age per year (OR, 1.03; 95% CI, 1.01-1.05), Pneumonia Severe Index score (OR, 1.01; 95% CI, 1.00-1.02), the presence of chronic lung disease (OR, 1.85; 95% CI, 1.03-3.30), and creatinine clearance (OR, 0.99; 95% CI, 0.98-1.00) were significantly associated with failure in the univariate analysis. When the Pneumonia Severe Index score was excluded to avoid collinearity with age and sex in the regression model, only male sex (OR, 1.92; 95% CI, 1.08-3.49) and age (OR, 1.02; 95% CI, 1.00-1.05) were associated with failure in the multivariable analysis., Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, among patients with CAP who reached clinical stability after 3 days of antibiotic treatment, only male sex and age were associated with higher risk of failure, independent of antibiotic treatment duration and biomarker levels. Another randomized clinical trial is needed to evaluate the impact of treatment duration in populations at higher risk for treatment failure.

Background: Shortening the duration of antibiotic therapy for patients admitted to hospital with community-acquired pneumonia should help reduce antibiotic consumption and thus bacterial resistance, adverse events, and related costs. We aimed to assess the need for an additional 5-day course of β-lactam therapy among patients with community-acquired pneumonia who were stable after 3 days of treatment., Methods: We did this double-blind, randomised, placebo-controlled, non-inferiority trial (the Pneumonia Short Treatment [PTC]) in 16 centres in France. Adult patients (aged ≥18 years) admitted to hospital with moderately severe community-acquired pneumonia (defined as patients admitted to a non-critical care unit) and who met prespecified clinical stability criteria after 3 days of treatment with β-lactam therapy were randomly assigned (1:1) to receive β-lactam therapy (oral amoxicillin 1 g plus clavulanate 125 mg three times a day) or matched placebo for 5 extra days. Randomisation was done using a web-based system with permuted blocks with random sizes and stratified by randomisation site and Pneumonia Severity Index score. Participants, clinicians, and study staff were masked to treatment allocation. The primary outcome was cure 15 days after first antibiotic intake, defined by apyrexia (temperature ≤37·8°C), resolution or improvement of respiratory symptoms, and no additional antibiotic treatment for any cause. A non-inferiority margin of 10 percentage points was chosen. The primary outcome was assessed in all patients who were randomly assigned and received any treatment (intention-to-treat [ITT] population) and in all patients who received their assigned treatment (per-protocol population). Safety was assessed in the ITT population. This study is registered with ClinicalTrials.gov, NCT01963442, and is now complete., Findings: Between Dec 19, 2013, and Feb 1, 2018, 706 patients were assessed for eligibility, and after 3 days of β-lactam treatment, 310 eligible patients were randomly assigned to receive either placebo (n=157) or β-lactam treatment (n=153). Seven patients withdrew consent before taking any study drug, five in the placebo group and two in the β-lactam group. In the ITT population, median age was 73·0 years (IQR 57·0-84·0) and 123 (41%) of 303 participants were female. In the ITT analysis, cure at day 15 occurred in 117 (77%) of 152 participants in the placebo group and 102 (68%) of 151 participants in the β-lactam group (between-group difference of 9·42%, 95% CI -0·38 to 20·04), indicating non-inferiority. In the per-protocol analysis, 113 (78%) of 145 participants in the placebo treatment group and 100 (68%) of 146 participants in the β-lactam treatment group were cured at day 15 (difference of 9·44% [95% CI -0·15 to 20·34]), indicating non-inferiority. Incidence of adverse events was similar between the treatment groups (22 [14%] of 152 in the placebo group and 29 [19%] of 151 in the β-lactam group). The most common adverse events were digestive disorders, reported in 17 (11%) of 152 patients in the placebo group and 28 (19%) of 151 patients in the β-lactam group. By day 30, three (2%) patients had died in the placebo group (one due to bacteraemia due to Staphylococcus aureus, one due to cardiogenic shock after acute pulmonary oedema, and one due to heart failure associated with acute renal failure) and two (1%) in the β-lactam group (due to pneumonia recurrence and possible acute pulmonary oedema)., Interpretation: Among patients admitted to hospital with community-acquired pneumonia who met clinical stability criteria, discontinuing β-lactam treatment after 3 days was non-inferior to 8 days of treatment. These findings could allow substantial reduction of antibiotic consumption., Funding: French Ministry of Health., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: Cotrimoxazole (Sulfamethoxazole-Trimethoprim, SXT) has interesting characteristics for the treatment of bone and joint infection (BJI): a broad spectrum of activity with adequate bone diffusion and oral and intravenous formulations. However, its efficacy and safety in BJIs are poorly documented and its use remains limited., Methods: We conducted a retrospective study in 2 reference centers for BJIs from 2013 to 2018 among patients treated with SXT for a BJI. Data were collected from patient's medical charts. Outcomes and adverse events were evaluated at day (D)7, D45 and D90., Results: We analyzed 51 patients with a mean age of 60 ± 20 (SD) years of which 76% presented with an orthopedic device infection (ODI). Gram-negative bacilli (GNB) were involved in 47% of BJIs (n = 24). Moreover, they were often polymicrobial infections (41%). Doses of SXT ranged from 800/160mg bid (61%; n = 31) to 800/160mg tid (39%; n = 20). Median SXT treatment duration was 45 days (IQR 40-45). SXT was part of a dual therapy in 84% of patients (n = 43), associated mainly with fluoroquinolones (n = 17) or rifampicin (n = 14). Outcome was favorable at D7 in 98% (n = 50), at D45 in 88.2% (n = 45) and at D90 in 78.4% (n = 40). The second agent combined with SXT was not an independent factor of favorable outcome (p = 0.97). Adverse events were reported in 8% (n = 4) of patients, with a median of 21 days (IQR 20-30) from SXT initiation and led to discontinuation (n = 3)., Conclusion: SXT appears to be effective for treatment of BJIs as a salvage therapy, even in GNB or polymicrobial infection, including ODI. Further data are needed to confirm SXT efficacy as an alternative oral regimen in BJIs., Competing Interests: The authors have declared that no competing interests exist.

Background: Infections complicate a minority of orthopaedic arthroplasties but are the leading cause of malpractice claims. The basis for the claims is unclear. The objective of this study was to identify the main deviations from current recommendations by reviewing patient files recorded by a major French medical liability-specialized insurance company for private practitioners (MACSF [Mutuelle d'Assurance du Corps de Santé Français]) and to analyze legal claims and outcomes of litigation., Methods: All claims data for periprosthetic joint infections were analyzed retrospectively from 2010 to 2014. Treatment strategies were compared with therapeutic guidelines published by medical societies., Results: Forty-five claims for periprosthetic joint infection were recorded; 82% of patients were men and the mean patient age was 63 years. Twenty-one patients (47%) had a knee arthroplasty, 21 had a hip arthroplasty, 2 had a shoulder arthroplasty, and 1 had an ankle arthroplasty. Twenty-three infections (51%) occurred within 1 month postoperatively. Staphylococcus aureus was isolated from intraoperative samples in 36% of the cases (including 25% of these with methicillin-resistant strains), and coagulase-negative staphylococci were isolated in 51% (44% methicillin-resistant strains) of the cases. Treatment lasted for a median of 9.5 months (range, 1.5 to 96 months), with a median of 6 months (range, 1.5 to 20 months) of antibiotics and 3 surgical procedures (range, 0 to 7 surgical procedures). A total of 18% of patients had antibiotic-related side effects, 2% of patients died, and 76% of patients had persistent sequelae. An infectious disease specialist's advice was required for 56% of the patients. Discordances with therapeutic guidelines were found in 76% of the patient files, including delay in diagnosis (44%) and inadequate medical treatment (18%) or medico-surgical treatment (13%)., Conclusions: Late diagnosis of early postoperative infections appears to be the major cause of inappropriate management and malpractice litigation. Discordance with current guidelines was identified. Early consultation with an infectious disease specialist may help to reduce malpractice claims., Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Background: In France, Carbapenem-Resistant Enterobacteriaceae (CRE) and Vancomycin-Resistant Enterococci (VRE) are considered as Extensively Drug-Resistant (XDR) bacteria. Their management requires reinforcement of hospital's hygiene policies, and currently there is few consistent data concerning the spontaneous decolonization in XDR colonized patients. Our aim is to study the natural history of decolonization of XDR carriers over time in a hospital setting in a low prevalence country., Material and Methods: Retrospective multicenter study over 2 years (2015-2016) in 2 different tertiary care hospital sites and units having an agreement for permanent cohorting of such XDR carriers. We gathered the type of microorganisms, risk factors for colonization and rectal swabs from patient's follow-up. We also evaluated patient care considering isolation precautions., Results: We included 125 patients, aged 63+/-19y, including 72.8% of CRE ( n  = 91), 24.8% of VRE ( n  = 31) and 2.4% ( n  = 3) co-colonized with CRE and VRE. CRE were mainly E. coli ( n  = 54), K. pneumoniae ( n  = 51) and E. cloacae ( n  = 6). Mechanisms of resistance were mainly OXA-48 ( n  = 69), NDM-1 ( n  = 11), OXA-232 ( n  = 8) and KPC ( n  = 3).Prior antibiotic therapy was reported in 38.4% ( n  = 48) of cases. Conversely, 17.6% ( n  = 22) received antibiotics during follow-up.Spontaneous decolonization occurred within the first 30 days in 16.4% ( n  = 19/116) of cases and up to 48.2% after day-90 with a median follow-up of 96 days (0-974).We estimated that XDR carriage was associated with a larger care burden in 13.6% ( n  = 17) of cases, especially due to a prolongation of hospitalization of 32.5 days (15-300)., Conclusions: Our study shows that spontaneous decolonization is increasing over time (up to 48.2%). We can regret that only few patients underwent screening after 1 year, emphasizing the need for more monitoring and prospective studies., Competing Interests: Not required; as part as routine care, all procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Not applicable. As a retrospective study, no consent was required. The authors declare that they have no competing interests. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Nocardiosis is a rare cause of infection that usually affects immunocompromised adult patients and might not be recognized by pediatricians. We report a fatal case of disseminated nocardiosis in a previously healthy child initially admitted for an abdominal mass with suspicion of a renal malignant tumor. The patient, originating from Mali without any medical history, displayed abdominal pain with progressive altered general status. Laboratory and imaging findings revealed lymphocytic meningitis and disseminated abscesses in the brain and the cerebellum and a large number of cystic lesions of the kidney. Despite being administered wide-spectrum antibiotics and antituberculous and antifungal therapies with an external ventricular drainage for intracranial hypertension, the patient died 6 days after his admission. Nocardia spp was cultured from a renal biopsy and the cerebrospinal fluid. Species identification and antibiotic susceptibility were obtained later, revealing a multidrug-resistant isolate of the Nocardia elegans/aobensis/africana complex. This case reveals the difficulties of diagnosing nocardiosis, in particular in children not known to be immunocompromised, because we face multiple differential diagnoses and the importance of treating nocardiosis appropriately because of intrinsic resistance issues., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2018 by the American Academy of Pediatrics.)

Background: Physicians are facing a worldwide increase in multidrug-resistant (MDR) organisms. Eradication of such bacteria, including so called superbugs (XDR), may cause physicians to prescribe last-resort antibiotics. However, experience with these drugs is limited and few data are available., Methods: A before and after retrospective study was conducted from January 2008 to June 2016. Prescriptions of parenteral antimicrobials considered as last-resort antibiotics (colistin, fosfomycin, tigecycline and temocillin) were reviewed by 4 infectious disease specialists (according to microbiology results, susceptibility testing, clinical situation and alternative agents), while doses were analysed by a pharmacist. As a second step, the cohort was split before and after 2013 coinciding with the arrival of a referent in antimicrobial stewardship., Results: The treatment of 77 patients with a mean age of 55.4 ± 18.7 years was analysed. The majority were treated for gram-negative rods (69.2%), especially Pseudomonas and Klebsiella spp. and Escherichia coli while 20.0% of patients were treated for gram-positive cocci (mainly Staphylococcus aureus) and the remainder were polymicrobial. Of 84 prescriptions, fosfomycin was the most frequently prescribed (47.6%), followed by colistin (40.5%), tigecycline (10.7%) and temocillin (1.2%). Outcomes were favorable in 75.3% of patients. In patients with MDR and XDR infections (n = 54), the mortality rate was 11.1%. After 2013, there were significantly fewer prescriptions of last-resort antibiotics for susceptible microorganisms (29.2% vs 6.9%), in the absence of supporting microbiology results (22.9% vs 3.5%) and fewer dose errors (56.2% vs 27.6%) (P = 0.02)., Conclusion: Reinforcement of the antimicrobial stewardship task force seems to be valuable for promoting the better use of last-resort antibiotics., (Copyright © 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.)

Objectives: To determine whether aztreonam is still an effective drug for the treatment of gonorrhoea., Methods: Observational study of patients with gonorrhoea diagnosed by urine multiplex PCR, with a past medical history of allergy to β-lactams or relapse after treatment with a third-generation cephalosporin. Patients received a single 1 g dose of aztreonam in accordance with the manufacturer's instructions., Results: Five patients (four males, one female) were enrolled, comprising two who were allergic to β-lactams and three previously treated with cephalosporins who relapsed. Median age was 38 years (range 23-51). Following treatment with aztreonam all were cured without any adverse event. All the men were free of symptoms, and the woman tested negative for gonorrhoea 1 month after treatment., Conclusion: Aztreonam appears to be an effective alternative to cephalosporins in the treatment of uncomplicated gonorrhoea, particularly when patients are suspected of being infected by strains with reduced susceptibility to ceftriaxone or are known to be allergic to penicillin., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

In attempt to identify the factors associated with delayed diagnosis during HIV infection, we studied retrospectively the epidemiological profile of HIV-infected patients diagnosed between January 1, 2012 and December 31, 2013 and followed in our clinical center in Paris. Data were compared to those obtained at the same site during the year 2003. One hundred eighty-six patients fulfilled the inclusion criteria: 49 (26%) had a CD4 count <200/mm 3 at diagnosis. Compared to subjects with CD4 count ≥200/mm 3 , advanced patients were older, had a higher plasma viral load, had more often an AIDS-defining event at the time of HIV diagnosis (45% vs. 3%), had been infected more often through heterosexual contact (69% vs. 44%), had less frequently past HIV testing (23% vs. 63%), and tended to live in less favorable conditions. A higher proportion of these patients initiated antiretroviral therapy in the 3 months following diagnosis (93.9% vs. 48.1%). Compared to data obtained in 161 patients in 2003, the proportions of advanced patients were similar between the two periods (26% vs. 22%). There was a significant increase from year 2003 to the 2012-2013 period in the proportion of men who have sex with men (MSM) (50% vs. 27%) and in the percentage of patients infected with HIV-1 subtype B (48% vs. 27%) and with positive syphilis serology (22% vs. 8%). Our data show that (1) HIV screening should be extended to populations with the following characteristics: older age, heterosexuality, and low socioeconomic level, and (2) HIV transmission continues to progress in MSM, arguing for the value of preexposure prophylaxis.

The use of antibiotics, as any other drug, is regulated by the terms of its marketing authorisation, notified in the Summary of Product Characteristics (SPC). If a prescription is not in accordance with the SPC, the physician prescribes off-label. There is very little literature regarding off-label use of antibiotics in adult healthcare facilities. A prospective monocentric study was conducted during 11 days from February to June 2015 in hospitalised patients from a tertiary teaching hospital with a high prevalence of multidrug-resistant organism colonisation to evaluate off-label use of antibiotics. Two independent experts assessed whether prescriptions complied with the latest guidelines in infectious diseases and whether off-label use of antibiotics was associated with an increased risk of adverse events. In total, 160 antibiotic prescriptions were analysed, of which 76 (47.5%) were off-label. Of the 76 off-label prescriptions, 50 (65.8%) were off-label regarding indications and 26 (34.2%) regarding doses. Nevertheless, 46/50 off-label indications (92.0%) and only 14/26 off-label doses (53.8%) were approved by experts, especially because of dose adjustment requirements. During follow-up, the rate of reported adverse events was not statistically different between patients with (n = 76) and without (n = 84) off-label prescriptions (P = 0.35). In a context of multidrug resistance and a lack of new drugs, high rates (47.5%) of antibiotic off-label use were observed in our hospital, but without an increased rate of adverse events. Moreover, 78.9% of off-label uses were in accordance with guidelines. Therefore, the SPC is not the warrant of an appropriate use of antibiotics., (Copyright © 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.)