Françoise Crokaert

Oral versus Intravenous Empirical Antimicrobial Therapy for Fever in Patients with Granulocytopenia Who Are Receiving Cancer Chemotherapy

BACKGROUND Intravenously administered antimicrobial agents have been the standard choice for the empirical management of fever in patients with cancer and granulocytopenia. If orally administered empirical therapy is as effective as intravenous therapy, it would offer advantages such as improved quality of life and lower cost. METHODS In a prospective, open-label, multicenter trial, we randomly assigned febrile patients with cancer who had granulocytopenia that was expected to resolve within 10 days to receive empirical therapy with either oral ciprofloxacin (750 mg twice daily) plus amoxicillin-clavulanate (625 mg three times daily) or standard daily doses of intravenous ceftriaxone plus amikacin. All patients were hospitalized until their fever resolved. The primary objective of the study was to determine whether there was equivalence between the regimens, defined as an absolute difference in the rates of success of 10 percent or less. RESULTS Equivalence was demonstrated at the second interim analysis, and the trial was terminated after the enrollment of 353 patients. In the analysis of the 312 patients who were treated according to the protocol and who could be evaluated, treatment was successful in 86 percent of the patients in the oral-therapy group (95 percent confidence interval, 80 to 91 percent) and 84 percent of those in the intravenous-therapy group (95 percent confidence interval, 78 to 90 percent; P=0.02). The results were similar in the intention-to-treat analysis (80 percent and 77 percent, respectively; P=0.03), as were the duration of fever, the time to a change in the regimen, the reasons for such a change, the duration of therapy, and survival. The types of adverse events differed slightly between the groups but were similar in frequency. CONCLUSIONS In low-risk patients with cancer who have fever and granulocytopenia, oral therapy with ciprofloxacin plus amoxicillin-clavulanate is as effective as intravenous therapy.

Vancomycin versus Placebo for Treating Persistent Fever in Patients with Neutropenic Cancer Receiving Piperacillin-Tazobactam Monotherapy

This prospective, double-blind trial assessed whether the addition of a glycopeptide would be able to reduce the time to defervescence in neutropenic patients with cancer who had persistent fever 48-60 h after the initiation of empirical piperacillin-tazobactam monotherapy. Of 763 eligible patients, 165 with persistent fever were randomized to receive piperacillin-tazobactam therapy plus either vancomycin therapy or placebo. Defervescence was observed in 82 (95%) of 86 patients in the vancomycin group and in 73 (92%) of 79 patients in the placebo group (P=.52). The distributions of the time to defervescence were not statistically significant between the 2 groups (estimated hazard ratio, 1.03; 95% confidence interval, 0.75-1.43; P=.75). The number of additional episodes of gram-positive bacteremia and the percentage of patients for whom amphotericin B was empirically added to their therapy regimen were also similar in both groups. This study failed to demonstrate that the empirical addition of vancomycin therapy to the treatment regimen is of benefit to persistently febrile neutropenic patients with cancer.

Infusion of Mesenchymal Stromal Cells can Aid Hematopoietic Recovery Following Allogeneic Hematopoietic Stem Cell Myeloablative Transplant: A Pilot Study

Mesenchymal stromal cells (MSCs) are important in the support of hematopoiesis. In this pilot study, we evaluated the safety and efficiency of donor-expanded MSC infusion after allogeneic hematopoietic stem cell transplantation (HSCT) in six patients with poor hematopoietic recovery. MSCs were infused without HSC and without conditioning at a dose of 1 x 10(6)/kg weight. Two patients displayed rapid hematopoietic recovery (days 12 and 21), and four patients showed no response. The two patients who showed hematopoietic recovery were in first complete remission (CR1) compared to the other heavily pretreated patients. There were no toxic side effects linked to MSC infusion. One patient developed cytomegalovirus (CMV) reactivation 12 days following the MSC infusion and died from CMV disease. We found that infusion of MSCs without HSC co-infusion can restore medullary function in some patients with poor hematopoietic recovery. Our data suggest that patients with a less damaged stroma could benefit from this approach.

Preemptive management of Epstein-Barr virus reactivation after hematopoietic stem-cell transplantation.

Background. Epstein-Barr virus (EBV) reactivation after hematopoietic stem-cell transplantation can lead to posttransplant lymphoproliferative disease (PTLD), which carries a high mortality rate. Among therapeutic and prophylactic options being developed, B-cell depletion with monoclonal antibodies is encouraging. Because viral load after transplantation is correlated with PTLD occurrence, we developed a preemptive attitude based on polymerase chain reaction (PCR)-guided rituximab administration. Methods. We monitored 115 transplant patients with a quantitative PCR for EBV DNA performed on whole-blood samples. Criteria for treatment initiation were a single PCR above 40,000 DNA genome copies per milliliter (gCop/mL) or two rising values above 10,000 gCop/mL. Weekly rituximab infusion at the dose of 375 mg/m2 was administered until negative PCR results were available. We evaluated the incidence of EBV reactivation and PTLD development. Results. Nineteen patients (16.5%) met the criteria for treatment. Incidence of reactivation was the same in high-risk and standard-risk patients (12 vs. 7, P=0.38). One patient developed PTLD after discontinuation of therapy due to a serious adverse event. No other serious adverse events were noticed. Viral load disappeared after a median of three cycles of therapy, and weekly monitoring allowed prompt intervention. No PTLD-related death was observed, all-cause mortality in the treated population was 68%. Conclusions. Our PCR-guided and rituximab-based preemptive approach to avoid PTLD after allogeneic hematopoietic stem-cell transplantation is feasible but probably overtreated patients. Prospective trials are strongly needed, they should use uniform PCR techniques and consider higher threshold values for treatment initiation.

Real-Time PCR for Determining Capsular Serotypes of Haemophilus influenzae

ABSTRACT A two-step real-time PCR assay targeting all six capsulation loci of Haemophilus influenzae (i.e., serotypes a to f) was developed and compared with a previously published qualitative PCR assay by using 131 H. influenzae clinical isolates. There was a 98.5% concordance between the two tests. The sensitivity of detection of capsular type-specific reference strains of H. influenzae a to c (101 CFU/PCR) was higher than that for type e (103 CFU/PCR) and types d and f (104 CFU/PCR), and a broader dynamic range was obtained (5 to 8 log10 units). No cross-reaction was observed with bacteria commonly isolated from the respiratory tract. We showed that both PCR assays are more reliable than slide agglutination serotyping. The real-time PCR-based assay seems to be an alternative of choice for the epidemiological follow-up of H. influenzae invasive infections.

Febrile neutropenia in children

Fever is frequent in neutropenic patients and often related to infection. Two major concepts, have contributed to the marked mortality decrease of those patients by the end of the 1960s: firstly, the duration and severity of neutropenia were the most important variables linked to infection and secondly, prompt administration of broad-spectrum antimicrobials empirically, was life-saving. At the same time it was universally admitted that a careful daily examination of all portals of entry for micro-organisms was mandatory and that laboratory and imaging investigations were needed at regular intervals, keeping constantly in mind the individual type and stage of immunosuppression. Through many studies, paediatricians contributed markedly in standardisation of management of febrile neutropenic patients. Neutropenic patients are not equally prone to infections, partly due to the underlying cancer, chemotherapy and co-morbidity factors. Neutropenic children are not only vulnerable to bacteria, fungi and viruses commonly encountered in adults, but also to common viruses and bacteria. Very few studies included a viral work-up. Epidemiological new trends are observed: Gram-positive bacteria and fungi are on the rise. Simplifying and shortening antibiotic regimens were made possible because new potent antibiotics were launched. Since the mid-1980s, many paediatric centres commonly discharge patients before complete bone marrow recovery, provided that patients meet certain low-risk criteria and do not exhibit any clinical or biological evidence of bacterial infection. However, a few prospective randomised studies have been conducted for assessing the safety of early antibiotics discontinuation and safe early discharge. The choice of oral agents up to now was complicated by the reluctance using fluoroquinolones in children. New challenges are numerous in terms of diagnostic tools, detection of epidemiological trends and emerging pathogens, identification and control of nosocomial threats including drug resistance, assessment of the real impact of prophylaxis, evaluation of new agents, the need for more accurate risk scoring systems, outpatient management and the necessity for an optimal use of resources.

In vitro activity of trovafloxacin (CP-99,219), sparfloxacin, ciprofloxacin, and fleroxacin against respiratory pathogens

There has been a steady increase in the number of hospital-acquired infections, mainly because hospitalized patients are vulnerable, compromised hosts in a hostile environment. In general, bloodstream infections are the second most common type of nosocomial infection, surpassed only by urinary tract infections. Banerjee et al. (4) found that the overall rate of hospital-acquired bacteremia, reported by the National Nosocomial Infections Surveillance hospitals in the USA, increased between 1980 and 1989 by 279% in small nonteaching hospitals and by 196% in large nonteaching hospitals. Another changing trend is the increase in infections caused by gram-positive bacteria. For example, between 1980 and 1989 the rate of infections caused by coagulase-negative staphylococci (CNS), Staphylococcus aureus, and Enterococcus spp. increased by 754%, 283 %, and 197%, respectively (5). The crude mortality rate for nosocomial bacteremia caused by CNS, Staphylococcus aureus and Enterococcus spp. was reported to be 45-55%, compared to 28-34% for that caused by gram-negative bacteria and 15-20% for that caused by Candida spp. (6, 7). Thus, effective eradication of these pathogens is of prime importance. Recent studies have shown that trovafloxacin has excellent broad-spectrum activity against both gram-positive and gram-negative bacteria (8, 9). Since nosocomial pathogens isolated from clinical specimens in the developing countries, including Saudi Arabia, are more resistant than those from the USA and Western Europe (10), we tested the antimicrobial activity of trovafloxacin against nosocomial blood culture isolates from 500 patients. We found this agent to have excellent activity against all of the gram-positive organisms tested, including methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, and Leuconostoc spp. Its overall inhibitory activity against all 573 organisms tested was superior to that of the other drugs with which it was compared.Thus, trovafloxacin appears to be a promising candidate for the treatment of serious bacterial infections.

Vibrio cholerae bacteremia in a neutropenic patient with non-small-cell lung carcinoma

Abstract.Vibrio cholerae was isolated from the blood cultures of a neutropenic patient treated with chemotherapy for non-small-cell lung cancer. Attempts to isolate Vibrio spp. from a rectal swab and stool were unsuccessful. Piperacillin/tazobactam treatment resulted in eradication of the microorganism from the patients blood. Although Vibrio spp. have occasionally been the source of infection in immunocompromised patients, this report describes the first case of non-0:1 Vibrio cholerae bacteremia in a neutropenic patient with a solid tumour.

Imipenem versus targeted therapy in cancer patients

In many instances, broad-spectrum antibiotics are initiated empirically in febrile cancer patients and continued for the whole duration of therapy. An alternative is to narrow the spectrum whenever the offending pathogen is identified. This study is aimed at comparing these two options. Non-neutropenic cancer patients with severe infections received empiric imipenem. After 72 h, those with microbiologically documented infection were randomized either to continue imipenem or to receive a targeted therapy. After 72 h of imipenem 76.1% were improved. After randomization, a higher efficacy was observed with imipenem (88.5 vs. 72.1%: P = 0.025). Bacterial and fungal superinfections were comparable. Costs were lower for targeted therapy in gram-positive infection and higher in gram-negative infection.

Outpatient and home parenteral antibiotic therapy (OHPAT) in low-risk febrile neutropenia: Consensus statement of a Belgian panel

Abstract Febrile neutropenia requires adequate antibiotic treatment. A subgroup of patients are only at low risk for complications and could be treated at home/as outpatients (OHPAT) after a short initial admission for work up. This position paper by a Belgian panel of experts presents criteria defining low-risk in febrile neutropenia, gives an overview of the existing experience and examines the present obstacles to a more widespread use of OHPAT in this country.